Personally? I'm hoping they ape Van Buren even more than they did with New Vegas.
Like many of you, I picture the game set in post-legion collapse territory, centered around Flagstaff. It's sufficiently far north to allow us to have a slither of Colorado, and thus include stuff like Burham Springs (albeit not in the location intended in Van Buren), and the New Canaanites.
House and the Courier won the day at the Dam, managing to negotiate the peaceful leaving of the NCR and Legion with Oliver and Lanius, with the Mojave serving as a buffer zone. However, Lanius's retreat was perceived as weakness. Lieutenants and Colonels all across the Four States declared themselves the inheritors of Caesar's mantel, in opposition to the Legate Lanius.
There are three primary "Legion" factions: Lanius, and the remnants of the army proper- wants to re-impose the old order of Caesar, though not too fond of Caesar cultists. There's Aurelius, a former Frumentarus who has come back from the NCR with very strange ideals indeed- republicanism. Republicanism by a council of military officers and aristocrats, true, but republicanism nonetheless. And the Boy-king- one of Caesar's few non-slave bastards. Revered by cultists of Caesar and Mars, but his rule extends only to Flagstaff. His strings are pulled by the Frumentarus Vulpes Inculta.
Another primary faction coming from outside the Legion is the Midwestern Brotherhood of Steel- formerly cowed by the Legion, they're now making a comeback. Their territory is like something out of the middle ages- vast fields of wheat attended to by ignorant peasants, lorded over by massive stone Redoubts. Their primary goal is to destroy the Legion, once and for all, conquer her lands, and secure an advanced piece of tech they believe is waiting for them...
And there is also you- you can choose to destroy all factions involved, destroy but one faction, or crown yourself King of the Legion.
There are also a variety of sub-factions- Mormons, NCR Rangers, Cassidy Caravans, Hubbologists
In broad strokes, it has a similar plot to Van Buren. You start the game as a Prisoner, and the ultimate MacGuffin is the B.O.M.B.