I personally think a low-fantasy/horror (possibly World of Darkness) game set in 16th-18th century would be cool. Many cool ideas at the time, lots of beautiful architecture and scenery to borrow from. I'd love to see a game which begins with subtle court intrigues, and a mysterious murder of a marquis at a ball rather than "here is a dagger, kill 5 rats".
One example to take inspiration from could be this film:
http://en.wikipedia.org/wiki/Brotherhood_of_the_Wolf
Probably not a recipe for a box office hit, but one can dream...
Also, in the latest version of World of Darkness, I find the Werewolf:Forsaken imagery the most powerful. A urban noir horror game based in that world, where combat is turned based squad tactics would be great. The game could start with you discovering your werewolf heritage and being recruited into a low-ranking pack. You are given a small, mostly worthless territory by your mentors, an alpha pack. You police the spirit world, defend your territory against other WoD horrors, find a totem spirit, etc, and then the real plot begins when all hell breaks loose and you are forced to flee as the alpha pack is wiped out by.... something.