I recently considered whether my ancient habit of partitioning my Windows HDs still made sense in the modern (read: Vista) era.. I have decided to keep on doing what I have always done... C partition (nowadays about 36GB for x64, 4k clusters) for main portion of Windows, D partition (512k clusters) for relocated Windows "User" folders ("D" is for "data", E (4k clusters) for program files.. I just change the "C" to an "E" in the default install path whenever I install software. Many programs save stuff to their own folders, which I would not want to lose in the event I restore Windows. F is Surplus (4k clusters) for whatever... G stands for "Ghost" and is still Fat 32 (32k clusters). I keep my Ghost .exe there, along with my C drive back-ups, which I create with Ghost in DOS. I also have other things backed-up there, drivers, PIM data files, settings from various programs, etc.... and all of which is, in turn, backed-up to an external drive...
I agree with C1, if you have humongous files, why not set-up a partition with a larger cluster size as long as your defragger can handle it? It is my understanding that you will waste less space to "slack" and your HD will be able to access files more efficiently... I once read somewhere that XP runs more efficiently on a partition that has a decent amount of extra space... do not ask for a reference, bc I cant remember where I heard that, but I have gone with it.. usually use 10GB (4k clusters) for XP's C drive, and 5GB (4k clusters) for my venerable old friend, W2k Pro... and Vista seems right at around 30GB for x86 and 36GB for x64, for which I also create 4k clusters.
This scheme has just worked for me.. I make images of my C drive fairly often, keeping three or so at a time... and just never fight with Windows.. if I am ever baffled by what Windows is throwing at me, I restore to my latest Ghost image... I got a virus one time.. years ago when I was on dial-up... I simply restored my C drive and away I went.