It's got to be Buffy the Vampire Slayer, from Eden
This is not an easy decision, mind you. Looking over the bookshelves in my study (which are only about half of my RPG accumulation), I own four versions of Star Trek RPGs, three Star Wars, three DC Comics, four Marvel, Ghostbusters, The Authority, Two Game of Thrones/A Song of Ice & Fire, Mouse Guard, James Bond, two Lord of the Rings, Deryni, Solomon Kane, Conan (two games), Atomic Robo, the Laundry, Leverage, Serenity, Battlestar Galactica, and the granddaddy of them all, Call of Cthulhu. There are a lot of terrific games on that list, and a few not so great. But I keep coming back to this one.
It’s a snap to GM and versatile enough (with Angel) to handle pretty much the entire range of Cinematic adventure. One of my favorite campaigns that just didn’t take wing for a number of reasons was a Buffyverse/Lovecraftian mash-up that had a new Slayer beginning her freshman year at the University of Massachusetts – Arkham, aka “Old Misk.” Sadly, it withered and died after about four sessions, but it’s one I’d resurrect in a heartbeat for the right group of players.