First, the targeting rule. I think the best rule change would be to make it like basketball, where you have a flagrant targeting, which is ejection, and non-flagrant, where it is just a normal foul — though they can still use replay to determine targeting.
Second, they need to change the rules about penalties near the end zone — particularly on an offensive team inside the 5 or 10. The issue is, half the distance — particularly with the current advantage offenses seem to have — isn't that big a deal. Instead, it actually almost encourages players to "foul" (aside from holding or grounding, where you can be assessed a safety). For example, why not run a pick play — chances are it won't be called and can get you an open receiver; and even if it is called you lose a yard or two.
I'd like to see a change where there is an actual penalty is assessed — for example, maybe you get half the distance and the rest of the penalty is assessed by moving the 1st down markers. To prevent it from being to severe, maybe make that, if it is half the distance, then the 1st down marker is moved 5 yards out — so if on a 1st and 10 play, a penalty by the offense gives a 1 and 15.