I'm gonna go ahead and second a new Fallout game built by Obsidian as NV was excellent. Jade Empire 2 is also a go as far as cool things is concerned.
But more importantly: Wing Commander VII (or whatever number they're on)! And none of that CGI crap for the cutscenes. I want live actors, bad sets, bunk beds, ridiculous Top Gun-style plots and Biff F-ing Tannen.
I also want Quest for Glory VI, a new Leisure Suit Larry game with Al Lowe actually writing the thing again, a whole buttload of surprisingly entertaining The Learning Company games and the Klopman diamond. Sorry, got carried away there. I mean the Klopman diamond II.
And since I'm on the subject of awesome things that will never get made, how about Skyrim...IN SPACE?!?!?!?! No? Really? Aw...
Edit: And now I feel like I have brain damage. Bulletstorm II! Even though the first one apparently sold terribly, it's still a delightful game.