A setting I've long thought fascinating would be the borders of the Byzantine and Sassanid empires in the early seventh century AD. It'd be almost ideally suited for a Darklands-type game, maybe with a little Mount and Blade thrown in. Two massive empires, each seeking to recapture and expand on the glory of their predecessors; religious border conflicts that are not only more complex than X vs Y, but contain conflicts within each and every side (in the north, Christianity vs Zarathrustanism; head west and it's emerging Catholicism vs emerging Orthodoxy; head east and it's Zarathustrans vs Hindus, with the odd Buddhist and Jain as apparently the Sassinids were playing religious bingo; the center, Assyrian Christianity vs Chalcedonian (well, okay, technically Nicene, but that's really splitting hairs); in the south, Jews struggling to integrate and keeping their heads down, and some odd, wild rumors of a new faith spreading in the Arabian peninsula...); lots of wonderful philosophical questions of culture and identity; just a fascinating time and place all around. And then, BOOM! Up ride the Arabs and turn everything upside-down, which just tosses in MORE interesting situations.
Of course, something that's that 1. in-depth and 2. dealing with politically and religiously sensitive themes would probably never get made; or, if it was, published. It's still a fascinating setting. My other idea is probably much easier, since it doesn't feature any cultural elements at all: think a cross between SimLife and Designasaurus, but set in the Permian. To hear most people tell it, life essentially went from amoebas to jellyfish to dinosaurs to mammals, with nothing in between. This is not only sad, it's hideously inaccurate; the chance to show off more would be great, the chance to change it up even more so, especially when you're working with environmental conditions most people are wildly unfamiliar with.
Some other ideas:
-Intrigue in the Ottoman court at the height of their Empire.
-Novgorodians fighting off Crusaders (we've all seen the Battle On The Ice, now fight it!).
-Playing as the active controller of a human immune system.
-(If we can go fictional) A thriving, if simplistic, theropod society after the meteroite impact.