The first thing I always do when I start a game for the first time is open the options, and look at everything, and fiddling with the graphics options, I always remap a bunch of the keys to make things easier or more comfortable. I get annoyed if I can't remap keys (LOOKING AT YOU ROBOCRAFT).
I always remap forward/backward to s/x, freeing the entire qwer row for abilities (or leaning, but few games have leaning). In the Witcher 2, for instance, I mapped each sign, in order, to one of qwert (so they cast when I press that key, rather than having to be selected and then cast with another button). I remapped throwing/planting (bombs, knives, traps) to the middle-mouse button, and blocking to a button on the side of my mouse.
If there's an interact/use/get-in-vehicle key and it isn't sharing with another function (like in the Arkham games and the Witcher 2), which usually defaults to e, I always remap it to c. I usually try to remap inventory to v (Witcher 2 didn't let me, unfortunately).
I remapped EVERYTHING in the console version of Injustice: Gods Among Us. I couldn't do combos fast enough when they were x/y/a/b, so I changed the attack buttons to the shoulder buttons and left trigger (and the power to right trigger), and moved all the other things to x/y/a/b, with the super move that you can do when your meter is full set to x+a, so I can just push both easily with my thumb to do it.