Off the topic of alignments...
I think the one thing that needs to be changed, beyond anything else, is Armor Class and how combat is handled. Sure you can have feats that increase your armor class, but its just not the same as when I get the chance to actually make a defensive action and control my character when someone attacks me. In other words, incorporate defensive or reactionary actions into the game and not just use Armor Class as a defunct, mundane, and boring defense game mechanic. I know the DMG has an option for optional defense rolls, which my groups use all the time...but if there was an official rule with optional defense maneuvers, and they can somehow make the game a little more cinematic than "I hit or miss, I do 14 pts damage," that would be awesome.
Sure, some of you will say that you can embellish it with descriptions, which we do and have lots of fun with, but it is just not the same. Period. Incorproate defensive actions, like a real parry or dodge game mechanic, make a defensive roll based on that, or base it off Reflex save, then you got a good game mechanic.
Everything else I mentioned above for changes would also apply, but if I have to limit it down to one single thing, its Armor Class and Defensive and reactionary actions to situations in combat, and to make combat more cinematic and fast paced.