So my friend (or so I consider him) Tetsubo kindly left me a couple of comments on my recent postings and that got me thinking about a different take on running a Call of Cthulhu. I would start with a futuristic setting where Humanity has spread out amongst the stars. Then an interdimensional rift occurs and connects this universe to the Other universe, which is populated with the Elder Gods, Mi-Go, etc. and human civilization begins to collapse. After decades of horror, the rift disappears (apparently). Now the survivors on one planet are putting the pieces back together and reaching out to find out if there are any other survivors out there, or at least search for needed supplies and resources.
This concept is obviously like the Space Hulk/Warhammer 40K game I posted about earlier. But instead of using the WH40K setting, which I find very restrictive as a GM, you could use a more "normal" futuristic setting for the background. One major difference would be factoring in the aftereffects left by the taint of Cthulhoid influences. The basic race would be humans, but you could also have robots, cyborgs, and androids. And then there would be human mutants, the insane, and the possessed. The only intelligent non-humans would be hostile ones from the Other dimension--that gives it a "not politically correct" spin, but one good for providing a pulp horror feel.
I would have the game set on one planet and tell the players that it is the only known planet not destroyed or overrun by evil things. That makes the universe seem colder and scarier, provides a feeling of vulnerability (in a strategic sense), and gives them a reason to care about it which can make for good heroic roleplay. However, their home planet will contain the taint of the Other still hidden away in places you'd least expect it. Their home base isn't totally secure--just deceptively so.
The universe outside will have everything from worlds where everyone is dead but the monsters, planets overrun with monsters, places where the aliens dominate a conquered human population, cultists (even entire planets full, complete with battlefleets), places full of the insane, etc. All this would provide a creepy, depressing, desperate vibe to the game quite different from the cartoonish, wargamey vibe of the Space Hulk/WH40K game I posted about earlier.
Or you could just go ahead and play CthulhuTech, which I want to do a mini-campaign of for my Wednesday night group.