I'd like to see better RPG mechanics, including the return of "traits". By this I mean things like having real differences between character builds (science guy, diplomat, sniper, etc.), rather than being able to make a jack of all trades character no matter how you start out.
Hopefully they'll improve on the main quest, which was poor. The fact that they changed the ending in one of the expansions speaks volumes to me.
I'd also like them to slightly change the combat, a lot of the weapons seemed really weak due to having to empty a clip into the head of a supermutant to kill it. Despite this, I never felt in any danger in the game, since I could also take vast amounts of hits.