A basic disc check or something like that to prevent the most basic piracy by clueless kids.
Any more than that is pointless, since if a person's technical knowledge has reached the point where he can look up and download a crack, any DRM I might think of will be rendered useless. At the same time, if an individual doesn't have the basic knowledge to find and download a crack, then even the most basic copy protection will stop them from pirating.
Beyond that, I'd focus on preventing Day 1 (or earlier) piracy.
This I would achieve by making the non-intrusive DRM that I'm using embedded in multiple files and would task programmers to make it as time-consuming to remove as possible. Also, I would make each game a minefield of glitches and bugs activated when the disc is copied (like the Arkham Asylum thing). While all this WILL be circumvented eventually, it will slow down the process of achieving a fully functional pirate copy, hopefully delaying the pirates by up to a week. This will have a positive effect on my sales.
I'd look into providing superior service, with free DLC, frequent and expedient patching of any problems in the game and online community support. I'd make people wish to buy the original game and give me their money. And I'd reward them for it.
But yeah, reading this thread I can see a lot of people don't seem to support the "Provide a superior product/service" approach and instead try to think of ever more convoluted DRM plans. Seriously, dongles?
EDIT:
I'd bring back cartridges. Yes, even for PCs. That'd make pirating trickier...
