Skyrim's art director Matt Carofano has confirmed that the game will be a single Xbox 360 disc. Given how enormous the game's world is, that's a pretty impressive feat of engineering.
300+ hours of gameplay mashed into one disc is ridiculous. Bethesda produced and Id Software developed RAGE is a game of comparison. RAGE is recommend to be installed into the harddrive so that the disc doesn't take all the attention and have the heavy workload. I know I'm going to install Skyrim into my 360.