SD's solution is right as far as using a USB caddy, you should do that, except I would use one of the 320Gig drives and not the big one.
One issue is that the registry *might* throw a wobbly if you move things from one drive to another. Depending on the program, and some can be REALLY fussy, re-installing them might be the only solution (make sure you copy any important data to somewhere else so you can paste that into the new directory!!). But many programs will, because they will pop up a request box asking where the darned thing is, rewrite the path, etc, to the registry once you tell the program where to look.
Oh, NEVER use the full capacity of a hard disk. That will cause all sorts of issues. Also, never "mirror" or ghost the whole drive. Just look at what is the important stuff, like documents/pictures/music/movies/yadayadayada and keep a copy of them. Everything else can be reinstalled IF a disk decides to die (and if you fill it so there is no free space then it will die). The other advantage of doing things that way is if you get hit by a virus/trojan/malware then your backup will not put the damn thing back onto your machine when you restore things after such an attack (which is why I never use "system restore").