As said Fallout3 and Fallout New Vegas are worth a look. Lots of DLC available for Fallout3 and some for New Vegas too (as if the games weren’t big enough already).
Borderlands is good too. Its similar to Fallout3 with its character development but its a lot lighter and more “fun” to play. Some great little comedy moments in it and also lots of DLC available as well. It also has a ridiculous amount of guns in it which dispatch people in some rather amusing ways.
Also another recommendation for Orange Box, plenty to keep you going with that little package plus Portal 2 comes out this week (well worth taking a look at, but play Portal 1 first so you can experience the initial wierdness…and cake)