One thing I'd like redone (and I believe Yahtzee mentioned this in Extra Punctuation), is the conversation threads. For me, it seems weird that Bethesda wants to take the idea of "face-to-face" conversation a bit too literally. Sometimes, I catch myself shrinking back when a conversation starts and the camera quick zooms to someone's ugly mug. I would prefer the style of KoTOR when the person was looking off-camera at the main character. Not only that, but then you got to see the main character answer back. With all the hard work I spent perfecting my char's face, it'd be nice to see it on-screen more often.
As for locations, I think the time is right to go international. Where have we been in the past few games? Southern California(F1); Reno, San Francisco, and Oregon(F2); Chicago and the surrounding areas (Tactics); DC and most of Maryland (F3); Pittsburgh (The Pitt); and Alaska(Operation Anchorage).
Other than Texas, New York and Vegas, there's really no other place I can think of in the U.S. to do a decent story in. My vote is China.