Being a unique American places, let's go Detroit.
Think of it, we have the ruins of a large city with large opportunities for factories, gangers, and pre-war tech (I mean, being a major production station of the 50's might give it an advantage). The conflict could be a lot like F3, but changed with different tech and the changes that could have occurred from the Vault Boy (Or Girl). Outside of De-twa, we could have a host of wilderness for mutants and the remnants of the suburbs now housing communities of vault dwellers and ghouls. Players could also go to Canada and finally experience the Commonwealth, with the further expansion of cyborgs conflicting with whatever old BoS/Enclave remnants. For money senses, DLC could involve the Upper Peninsula, Lake Michigan, the conflict of BoS and Enclave in Chicago, or further along the Saint Lawrence Seaway.
I really just want to see what the Commonwealth is, as a new power. I mean, the Fallout universe is drifting away from the past to the future (as seen with the NCR on the cover of NV, not any Old American power), so employing the new civilization of the east would be fanciful. If it follows NV's choices, I guess you could either be Commonwealth, BoS, some residency of Detroit, or a large raider group, or the attempting to return Enclave.
Also, being Detroit, that would have to be some cars that could work. I wanna drive-by some peeps in the hood!