Personally I prefer a 3 tier system with a nominal size main hard disk (OS and Applications go here). A large size secondary disk (all big games go here). And then a third Good size back up disk (Self Explanatory(also a good place for downloading)). To make this easier I'll explain why in short reasons.
Restricting the main hard drive to OS and applications installs helps maintain the system performance as it's not being bogged down with too much data nor unnecessary read/writes.
Reserving the secondary big drive for games (takes up a lot of space) not only keeps it more organised and easier to keep saves (not counting those found in My Docs), but if you ever have to reformat your main drive, if you have a lot of games, it will cut your reinstall time by over half as when you got to reinstall the game, the installer already detects the games already installed and skips copying over files that are already on the disk. Bear in mind though, that many installer will reinstall files that don't match versions on disc so you will need to reinstall patches as well.
3rd tertiary backup disc is a must for backups such as your my docs, downloads etc. Also restricting downloads to the back up drive helps reduce fragmentation of your main system drive helping to maintain consistent performance. It is also a good idea for security concerns such as if you accidentally download a virus.
This type of setup also better distributes hard drive loads across drives improving overall hard drive life expectancies. And if one drive dies, at least it won't take all your data with it.
These are only a few of the benefits of running a 3 tier hard drive set up. Hope this helps.
