Sine Nomine recently released their new game, Silent Legions. It is a sandbox mythos game where almost everything, from aliens and cults to gods and conspiracies are designed by the GM before and during play. It has many tools in the form of charts and advice on how to play such a game. The rules for player characters can be used or replaced with another game, which makes it worth its weight in gold.
In the couple weeks I have owned it, I have come up with a variety of setting seeds and here are a few:
The PCs are SG-35 and are the unlucky ones to release an alien (god) and its minions. This is meant to replace the Ori. Cults form when the minions come to various worlds and show their superscience technology off and how it can "improve" the lives of the people. They are also scouting new food sources, i.e. the people.
After Sauron's destruction, Morgoth is ticked and sends a few minions that were sent into the Outer Darkness with him back to Middle Earth. One specializes in making monsters and the rest form cults to Melkor, a name that is long forgotten by men. Since the elves are gone and dwarves are fading, there are no strong allies for humanity. Orcs and trolls join with the cultists and work towards a future where the Valar fall.
Mars was colonized a few centuries ago and now the population has reached several million. It is self sufficient but still has economic ties to Earth and the other colonies. Then a mining robot breaks into an alien starship and parts of the colony goes crazy. The PCs are troubleshooters who are exploring some of the most alien, twisted places where the aliens have made themselves at home. There are no spells, just artifacts that represent alien technology. So Doom but with lots of people here and there (replacement PCs as needed).
A more standard mythos game, similar to Call of Cthulhu, but Madness (SL's version of sanity) is replaced with Humanity from the Sorcerer rpg. In other words, when the counter hits 100, the characters become something not human. They aren't gibbering in an asylum, they are monsters in league with the enemy and use their knowledge to promote the alien agenda.
The PCs are animals ala Watership Down or Secret of NIMH and humans are the mythos. Noble Wild should come in handy here if you want to try it with 3.5 or Pathfinder. Cults come in the form of human worshippers, much like that one group of rabbits that sacrificed some of their numbers for safety in Watership Down. Except these bunnies aren't just gaining security, they are being corrupted by human pollution, technology or even magic (the setting doesn't have to be modern day Earth, it can be anywhere and when).
As you can see, Silent Legions can be used to design many, many different kinds of games.