Post apocalyptic Cthulhu sounds pretty solid. The hopeless last days of man where the end isn't reckoned in the solemn perambulation of stars. It's already upon us and the story is simply a document of the last days. A very fatalistic setting I'm just curious how it would function if the elder gods were the actual vector of the fall; sounds like the agents would get stomped like nothing. I like the idea of Cthulhu in space as well but more as Star Trek: Enterprise, Kubrick's Space Odyssey's or Event Horizon than full blown Space Opera. There is something about exploration and being a pioneer into the unknown that make the concept more horrifying to me. High technology but travel in the stars still means isolation in the black.
edit: A Firefly-like setting would work well too. Isolated backwater settlements and reaver cultists? Hell yeah.