From Experience, I would say have a minimum of Four drives. :
(1) C Drive purely for Operating System Only
(2) D Drive for Program Files Only
(3) E Temp Drive
(4) F Data Only
If ever you have a system crash, your data is easier to recover.
C Drive should be kept lean as possible and well defragmented to ensure just the operating system files are retreived efficiently.
D Drive you will have to configure for temp storage. For folks who do not know, you will be amazed how much temp files are written to your Document and Settings area on the C Drive (eg, C:\Documents and Settings\<your username>\Local Settings\Temp). Totally unwanted\needed files that can be removed. More importantly, the default area can be changed. Right Click My computer --> Click Advanced Tab --> Environment Variable (bottom Left in XP) and Change User and System Variable for TEMP and TMP to your designated areas, for example a Temp Drive - E
E Easily navigated to for deleting purposes
F Easy to recover and transfer.
If you don't have the luxury of having 4 separate drives, partition the primary into secondaries acheiving your required additional drives, or like me use a tool such as Partition Magic.
Another hopeless set of folders and files are windows update. When was the last time a windows update was backed out? Me? never! Well the backup files are kept in the root of your c:\Windows directory. You will need to be able to see hidden files or folders but if you see lots of folders like '$NtUninstallKB946648$' then delete them if they are very old because they consume large amounts of diskspace. If you're not sure, then atleast move them from your C Drive.
For Advanced users, I would recommend PowerToys from Microsoft. A good tool allowing a user to make config changes to folder destinations.
Hope the above helps.