In Nomine was and is the RPG I have run most successfully. It has a wealth of background and setting that can suit most tones, be they light, dark, comical and so on. The system is simplicity itself with 3 dice deciding most things.
The basic setting is a great premise, the world’s oldest war between heaven and hell continues on to this day as a cold war. Earth is a Casablanca with agents of both sides of the war influencing the humans.
The real shining gem of game design meeting fluff is the mindsets of the different sorts of angels and demons. It gives a great base for players to role-play from. A good example is the choir of Seraphs angels of truth they can see the truth in the universe and it hurts them to lie. By contrast equally interesting is the fallen Balseraphs, they too do not lie; they believe what they say to you and force you into their world view.
In the time I've been gming In Nomine I have seen it run zombie games, mythical games, action games, low powered humans games and high power American gods style games. On the whole it is extremely versatile for any genre you may want to run.
The only criticism I have is the art. The original soft cover had a beautiful piece of art of a flaming feather and the layout of the book was also spot on. But I really dislike SJ Games line art that is through out the rest of the book, it's overly simplistic and cheesy and gives the wrong visual tone to the entire book. It you want to make your eyes bleed have a look at the GM Screen.