Start by really thinking through what a post-apocalyptic society would need to survive. Think about what life in such a society would be like, and then create the environment around that model. Think about the economics of subsistence/scavenger living, and think about the sustainability of survivor communities.
I think that's one thing that New Vegas did better than FO3 - presenting a society that actually made sense in terms of population, economics, technology, and so on. For example, places like Big Town are hard to believe in simply because their existence is so fragile. Also, the casualty rates of the Fallout games is way to high for a population that small.
So, all of these things have to be thought through before they start developing the setting.
As for the rest - I wouldn't mind more of the same, really. Maybe a little tighter gunplay in line with that one FO3 mod that added insta-kill headshots and the like. Obviously, engine tweaks to improve performance and graphics. But aside from that, more of the same is fine with me.
Oh yeah, nearly forgot -- more and better factions and factional rivalry. That goes for all Bethesda games.