1: Virtual Steelport is completely saturated with activities and collectibles, with more unlocking the further you progress in the game. Don't run around completing activities and gathering collectibles right off the bat. You don't have to AVOID collectibles, just don't bother going on a massive hunt yet. Explained in rule 3.

2: Most Side Quests are nothing more than a chain of activities. Waiting until you have the Side Quest will allow you to hit most if not all activities, while experiencing some interesting dialogue with the various Side Quest givers. If you have already completed the activities the Side Quest deals with, you'll end up just going to the quest giver and turning it in. This allows the potential to complete a bunch of activities, go to get a mission, and instead wind up turning in three in a row.

3: There are several types of collectibles, three of which require specific powers to obtain. You also obtain a Collection Finder from a side mission part way through the game, which allows you to click on Collectibles in the legend of your map to see the location of all the collectibles. Once you have all four of these things, you can embark on a single, glorious collecting crusade, as opposed to several loops around the city trying to spot things and being frustrated that you can't access some of them yet. One collectible type gradually appears as you progress through the game, but these are comparatively few in number and easy to obtain. Just consult your collectible finder now and then.

4: There are several challenges associated with weapons and powers. Find them, know them. Most of them require you to kill aliens specifically. Smaller challenges like 10 kills can be done relatively quickly just by obtaining high notoriety, but some of these challenges require upwards of 100-250 kills! Take advantage of the Virus Injection activities dotted throughout the map, as many of them spawn tons of aliens. This activity type disappears upon completion, so it may be beneficial to leave the mission area just before completion to fail purposefully, allowing you to farm alien kills and complete these challenges in no time.

5: There is also a challenge to travel quite a sizeable distance in alien vehicles. If I were to start over (and I assure you I most certainly will) I would take every opportunity that I weren't required to use a different form of transportation to travel in these vehicles. Get/unlock one as soon as possible, the easiest way is to get a level or two of notoriety and jack one. I would suggest the car, as clumsy as it is to me, over the flying vehicles, as it requires you to take roads. You'll be getting more distance per destination since you aren't flying as the crow, and it won't seem nearly as grindy if you work it into your normal routine. Otherwise you'll find yourself flying around in circles for hours just to get a quarter through this challenge and kicking yourself for it the enire time.

And that's it, just a few simple spoiler-free "I wish I knew" tips to enhance your experience. Enough reading, get to murdering.