I know it isn't the sexiest of issues, but I think fatigue/stamina is huge. Going all the way back to v1.0, the 50-man limit to the roster has been a critical element of the game. It impacts every aspect of coaching a team... recruiting, roster construction, game planning... everything.
If fatigue has no impact, the 50-man limit becomes meaningless, the importance of recruiting is diminished, etc. I am better off blowing my entire budget each recruiting season going after a few stars and trusting that I can hide the resulting AC-signed scrubs on my roster without fear of repercussion.
In my view, that has to be among the first things to be addressed. It, of course, would also be nice if we understood how pass coverage worked and therefore how to construct a defense, but first things first...