Feel free to comment and ask questions!
Enjoy the guide!

• Press and hold "R" to reset
  
  Re-Roll to get the right "Treasure Room"
  Just started and the first treasure room just contains "insert useless ♥♥♥♥-item here"?
  Hold "R" and erease those traumatic memories, start again and hope for better luck.
  Basically you can re-roll the 1st level until the treasure room contains the item you desire, just go on afterwards.
  Extremely useful when you're playing as "??? / blue baby" and "The Lost".
  
  
  Like here, i re-rolled the dungeon until the 1st treasure room had "holy mantle" (Negates the first damage taken in every room), takes about 10 minutes to get the item you want.
  (yea like 10 minutes -_- i was so unlucky that it took me 40 minutes to get the right start with "the lost" on hard, but it was totally worth it, it was the perfect run and i made it)
  
  
  
  
  
  
  Re-Roll to get the right "Sacrifice Room"
  Also you can seriously consider re-rolling until you have a "sacrifice room" near you at the start, they also can have some good starting items (dead cat e.g. is very useful when you play as "???" or "the lost") or even a red chest that teleports you to satan to make the deal of your life.
  Is very useful when you're doing challenges since you can't get treasure rooms and a nice sacrifice room or an awesome deal with satan can ease the challenge a lot.
  
  
  "Goat Head" (A Devil/Angel Room will always spawn after every boss fight, excluding the first floor and floors after UteroII/Womb II) is always a good start.
  
  
  
  
  
  
  
  
  
  
  Also worth knowing/doing
  
  
• walking through spikes
  
  
  When you encounter spikes like this, you can walk pass them and get possible items in the middle if you walk diagonal through, takes some practicing but it maybe worth it, there are often spikes like this where you can just walk through.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
• Trapped Golden Poop
  
  If you find golden poop like this, you actually can get some of the coins, just shoot the upper stone, the splashes will damage the poop and then walk close to the coins to pick some up.
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
• Trade bombs for bombs
  
  
  Here i took the screenshot too late, but i think you will get the idea, basically if you have 1 or more bombs and you see 1 single bomb behind some rocks, do the 1 for 1 trade everytime and destroy those rocks! First there is a chance that you get another item and second is that there could be a possible trap-door like in this screenshot and third it costs nothing so you only can win.
  
  
  
  
  Here you also "check" by placing the bomb there for "secret rooms" and it's basically for free.
  
  
  
  
  
  
  
  
  
  
  
  
• Dice Room Number Five
  
  
  
  
  
  
  Dice rooms are locked by 2 chains, needing 2 keys (see above).
  If you come across this room (Number 5), don't activate it immediately! First clear the whole level, boss included, also open the treasure room, because when you walk over this dice you reset the current floor and restart it. Awesome! You can get minimum 2 power ups again, 1 from the treasure room and 1 from the boss. Also you can buy stuff again at the shop. (Only worth doing from level 1 - 5, when you're at lvl. 6, don't go into the boss room since you can't come out again even after the fight)
  
  
  
• Things you want to do to ease the game(pain)
  
  
  • Spending Coins!
    If you have many coins, ♥♥♥♥ all your coins into the slot machine(s), because there is a chance to get "projectile protection" (a fly that flies in a circle around you, blocking projectiles, you can also get it from the pill with the "pretty fly" effect), you can have up to 3 of these and they make the game so much easier.
    3 PRETTY FLIES (or any other projectile protection) YOU SHOULD TRY TO GET THEM IN EVERY PLAYTHROUGH! (or any other 3 projectile blockers)
    So do this everytime you can (you will get almost everytime the chance in any playthrough, even several times.
    
    
  • Bombing everyting!
    
    If you have spare bombs, don't just bomb walls for "secret rooms", blow up:
    
    Stones: possible trapdoor to an item and also power ups from "tinted stones",
    Skulls: cards, runes, soul hearts and companion-babies
    Mushrooms: pills, trinkets and mushrooms (power ups)
    
    You should do this everytime you have 1 spare bomb, bombs are best used for this, damaging enemies with bombs is not that rewarding, so use 'em for blowing stuff up! Preferably mushrooms!
    
    Here i just bombed 2 mushrooms and i got 1 pill and the "magic mushroom" (all stats up), so bomb every mushroom you can!
    
    
    
    
    
    
    
    
    
    
    
    

Blank Card (Has the same effect as the card or rune you are currently holding)
Rechargetime : 4

This item can really be overpowered sometimes, just imagine holding "V - The Hierophant", which gives you 2 soul hearts or even better the "Jera"-Rune which doubles any pick-ups in the current room. (even shop pickups, means that when you use it in the shop e.g. a key will drop near the buyable key for free)

Unlock it by defeating Isaac in the cathedral with Eden.


Credit Card (Instantly buys all the items in the shop, allowing your character to pick them up for "free". You can also use it in the Devil room which allows you to pick the items up for free.)

If you find one credit card, wait until you've beaten the boss of the current floor, if you get a "devil room" and if there are even items to buy for hearts then you are in for a treat.

Unlock it by beating challenge number 10 (Cursed!)

• "Cathedral"[bindingofisaacrebirth.gamepedia.com]
  
• "Eden"[bindingofisaacrebirth.gamepedia.com]
  
• "Challenges"[bindingofisaacrebirth.gamepedia.com]

Besides the other characters, there is also some other stuff you should unlock, those items are really easy to get while playing, if you have spare bombs mostly, that's why i mention them.

Unlock it by simply destroying 100 tinted rocks total (challenges do not count)
Those are those slightly different rocks, they also have this little black "x" on it, like the one on the top left in the screenshot below.

If you're lucky enough to find it (if you have it unlocked, you can easily try to find it by blowing up these special rocks, drops pretty often), it gives:
Damage Up. Tears Up. Speed Down.















Unlock it by visiting 10 Arcades (challenges do not count)
Those rooms where you have to pay 1 coin to enter, just open 10 of them.

The Gamerkid turns you into a Pac-Man-like creature for 5 seconds, you gain invincibility, increased Speed, the ability to damage enemies by touch and you restore a half-heart of health for every 2 enemies killed. Enemies will also turn blue and start fleeing for the duration of the effect.


Unlock it by dying 100 times (challenges do not count)
I guess you know how to die in this game.

The Scissors seperates your head and body, you control the body and attacks fire tears from both body and stationary head.


Unlock it blowing up 20 shop keepers (challenges do count, just kidding, they don't)
You just need to blow up that creepy white corpse inside the shop.

It's a trinket and it:
Increases the chance to get a drop after clearing a room.
Increases the loot quantity from chests.
Although the Luck stat also influences this, it does not actually increase the Luck stat.
Pills have positive effects.


Unlock it by playing the shell game 100 times (challenges do not count)
It's the dude with the 3 skulls, play the game and may even win "Fly Love".


It's a trinket and it:
The wiki says it "sets your money to 35685326", but that is total bs. For what i know it's doing the same as in the game before, it gives a 50% chance of increasing the value of every coin pickup by one cent. Can be found in Golden Poop.

"Fly Love"[bindingofisaacrebirth.gamepedia.com]

Bob's Brain
(A Familiar that charges forward when you shoot tears and explodes upon enemy contact. The explosion is poisoned and can also hurt you. Comes back a few seconds after the explosion.)

Hard to hit moving objects and you also will hurt yourself, i guarantee it.
Yes you can open "secret rooms" by hitting an enemy right in front of a possible location, but it's really not worth it.

BUT if you can handle bob's brain, use it and blow some ♥♥♥♥ up!

It's your decission to use it or not, i just recommend to avoid it.


Like "Chris Pontius" said in "Jackass Number Two":
"Todays debate: Is it wrong to be strong? You be the judge."

Should you take them or should you avoid them?

I say "take 'em" and math recommends it too!
Because there are 27 different effects and only 8 are mostly really bad for you, 9 are kind of meh or useless and 10 are good or really good, so the odds are in your favor and if you really get a bad pill then you still know the pill and it's effect for the run so that you can avoid using them.

ONLY USE PILLS WHEN NO MORE ENEMIES ARE IN THE CURRENT ROOM OR YOU ALREADY KNOW IT'S EFFECT! (also you should only try an unknown pill if you have at least 2 hearts)




48 Hour Energy : Drops one to three battery charges, and fully charges spacebar item.

Balls of Steel : Gives you two soul hearts.

Full Health : Restores all red hearts.

I Can See Forever : Opens all entrances to the secret room and super secret room, but only for the floor activated.

Pretty Fly : Spawns a fly orbital. (Best pill of all right after "health up", if you get 3 of those flies then you're practically immune to tears, very very usefull for the later bosses)

Health/Luck/Speed/Tears/Range Up : Does what it says. (Best is obviously "health up", but NEVER GO FULL RED HEART! Leave at least 2 hearts that you can get "soul hearts" and "black hearts")

About NEVER GO FULL RED HEART:

You will see it in your current run, if you get enough red hearts or whatever hearts you get. Just don't max the red hearts out too early, better later (after "IT LIVES!" maybe).
And also as "Nani" said :"..I forgot that "take no damage" for the devil room chance only counts red hearts...".
If you take no damage to red hearts, you increase the chance of a devil room after beating a boss, soul heart or black heart damage (and certain items that prevent damage) do not count.




R U A Wizard? : Tears are shot diagonally, alternating between left and right. Lasts for roughly a minute. (Annoying, but you just can wait it off)

Bombs are Key : Switches number of bombs and keys. (Depends if it's good or bad)

Explosive Diarrhea : Upon use spawns 5 active bombs behind you. (Just get away, may use it for breaking stuff)

I Found Pills : Changes the appearance of your face. (yea only that)

Lemon Party : Spawns a large yellow pool around you. Greatly damages any enemy that steps on it. (If you want you can count it to "good effects" and also do not visit websites that are called lemon party! never!)

Paralysis : Prevents Isaac from moving for a short duration. (Just wait it off)

Pheromones : Charms all enemies in the room for a short period of time. (If you use it at first there are no enemies there anyways, at least should be)

Puberty : Causes you to grow four hairs from the top of your head and zits on the face. (yea only that)

Bad Gas : Isaac farts, poisoning enemies around him.




Amnesia : Replaces the floor map with a ? for the rest of the floor. (not that bad but annyoing, if you are still missing the secret rooms on this floor, then you only can grab a piece of paper and draw the map by hands)

Bad Trip : Injures Isaac by half a heart. If a Bad Trip pill is used while Issac only has a single heart left or less, the pill will give Isaac full health instead. (You first don't know the pill effect so you propably will take damage, that's why it's still bad and also instantly kills you when you play as the 11th character. But when you know the effect and you have 1 heart or less, then it's like "full health")

Hematemesis : Empties all but one red heart container and spawns 1-4 full red heart pickups. If Isaac only has half of a heart left, it will heal him to one heart. (Mostly bad, cause imagine that you're at 10 hearts and you use the pill, you're at 1 heart and maybe only 1 heart drops on the floor)

Health/Luck/Speed/Tears/Range Down : Does what it says. (Sucks in every case)

Key management is the key to winning.
Unless you start with "cain", your first goal should be to get a key to unlock the "treasure room" on the next floor and you should keep it going until you reach "the womb" (stage 7-8).

If you manage to get 1 key on the 1st floor, DO NOT waste it on the shop, unless you have 15+ gold (which is very unlikely, but not impossible).

If you get more than 1 key then you can decide yourself, based on your gold, if you want to use a key to open it.

Shops also have a chance of being replaced by a miniboss room containing Greed or Super Greed.

When you are low on keys (0-2) and you have the chance to trade 1 bomb to get 1 key, DO IT, regardless how many bombs you have.

• like here, place a bomb to get the key

• Greed[bindingofisaacrebirth.gamepedia.com]
  
• Super Greed[bindingofisaacrebirth.gamepedia.com]

Yes, try to get into every normal accessable room and clear out the enemies, at least until you reach "the womb" (stage 7-8).

You will get so many useful drops, maybe even the key or the bomb you were desperatly looking for.

• Maybe you will come across this room, mostly i think in "Necropolis", when you look closer you will realise that there is no way (unless you have flying) to get to the center, because when you bomb the 2 stones you dont create a bridge you can walk over, so don't get fooled.

• and yes, you will find rooms just filled with poop

I couldn't have done it any better than "OckerGui" with his guide "Secret and Super Secret Rooms - An Illustrated Guide", so please check his guide out for how to identify "secret rooms".

OckerGui's Guide

• You have to kill Mom once to unlock "the womb".
  
• You have to kill Mom's Heart 11 times to unlock "It Lives!" who will permanently replace the Mom's Heart battle.
  
• Killing "It Lives!" will allow you to access "Sheol" and "the Cathedral" using the stairway down or the beam of light that appear.
  
• Note that these levels can be reached earlier than this if a devil or angel room appear when you beat Mom's Heart
  
• Killing *insert boss01* in The Cathedral 5 times will cause "The Polaroid" item to be unlocked. This item will always drop after "mom" battle once unlocked.
  
• To access The Chest, you need to beat *insert boss01* and touch the chest while "The Polaroid" is equipped.
  
• Killing *insert boss02* in Sheol 5 times will cause "The Negative" item to be unlocked, it will always drop after the "mom" fight once unlocked.
  
• To access The Dark Room, you need to beat *insert boss02* and touch the chest while "The Negative" is equipped.
  
• Then find "Key Piece 1" and "Key Piece 2" by destroying angel statues in angel rooms (a boss will appear and drop the piece), then at the start of "The Chest" and the "Dark Room", open the golden door while you have both pieces, which grants you entrance to the FINAL BOSS of the game.
  
  If you have managed to do all this... CONGRATS! You will not get anything from beating the last boss, not even a lousy achievement, you only unlock the last ending and also before you unlock "dad's key", but for that you don't need to fight the last boss. At least you can finally play the game now.

By getting "Key Piece 1" and "Key Piece 2" you'll unlock "Dad's Key"



Effects:
Opens all locked doors, (Secret Rooms, Super Secret Rooms, Challenge Rooms, and rooms in the Chest)
Can be used to open the door to the FINAL BOSS of the game.
Has to be used twice to unlock special rooms with double lock (Dice Room, etc).

• Unlock "The Lost" and try to beat "Satan", "The Lamb", "Isaac" and "???" on hard.
  You will unlock some of the best items in the game (like "Godhead"), but it can be very challenging, i mean THIS IS SO F*CKING HARD! but totally worth it.
  
  How to unlock "The Lost" (also more detailed description)[bindingofisaacrebirth.gamepedia.com]
  
  
  
• Do all (other) challenges!
  
  All Challenges[bindingofisaacrebirth.gamepedia.com]
  
  
  
• Do the "boss rush" with every other character!
  (here it's recommended when you want to really just do a boss rush, that you "re-roll" until your first item is something very powerful, like "Ipecac" or "Epic Fetus", or any other item to kill bosses easily, you know best which ones you like the most now i guess)
  
  Boss Rush (detailed desc. of all unlockable items)[bindingofisaacrebirth.gamepedia.com]
  
  
  
• Unlock all the other achievements!
  
  All achievemnts, how to unlock and their rewards[bindingofisaacrebirth.gamepedia.com]

If you think there should be something added or maybe that some information is ♥♥♥♥, let me know in the comments.

Thank you for reading this guide :3