I've really enjoyed GTA IV, but Liberty City is my least favourite setting, both in GTA III and IV. I think that GTA is at its best when it's in an environment that helps the humour of the game come through, like Vice City; so a return there would be good, or maybe a larger version of Las Venturas in the Seventies.
I like the idea of being able to move between cities that has been suggested by some other people. Perhaps starting in a smaller town in America, moving to one of the big cities I mentioned above, and perhaps having to go to Sicily to do some missions for a family over there. But that would be quite ambitious, and I think we can expect a couple of iterations that don't innovate too much; so I'll save that for GTA V.
Oh, and let's not get in to a big debate over who drives on the best side of the road. They're both good sides of the road.