Fallout: Texas. Seriously. Look at a map. So much to work with in the Houston - San Antonio - Dallas/Ft Worth triangle (including Austin). Houston would have probably been hit the hardest so that would be the most irradiated (and probably the most difficult) area.
Replace Speech. I only hate it because of New Vegas requiring it for any ending I desired. And I think it isn't impossible to replace. Just have more dialogue checks based on skills or SPECIAL that most closely relates to the topic at hand. There was a minuscule amount of this in NV and I felt that more would have been great. Some dialogue checks could even require a combination of skills/SPECIAL with enough points.
Everyone has said it so far, but because I have felt it since seeing motorcycles just sitting there in Fallout 3, the ability to repair and drive one. If your repair skill isn't high enough, make it really expensive to have someone fix it for you.
Time to progress throughout a play through, whether from sheer amount of time played, to plot mechanic. Fallout 3's intro was awesome for this. You got older. I would love to see something similar, albeit not as abrupt, occur throughout the entire game. I'm sure it would have to be limited so that older NPCs wouldn't just die out before you can get to them because you faffed about too much beforehand.
Extend character creation into your origins, even if only a little. Give a little more variety and choice to the player.
Oh, and some freaking co-op. Even if it's just letting a friend temporarily take control of your follower.