I used to use multiple drives on my working desktop system, but after moving to smaller form factors in the past five years or so, have used a single 2TB drive with 3 partitions. C: is under 100GB, and has system, software and critical or frequently used data (work/accounting/correspondence, etc.). The remainder of the drive is divided roughly equally between two data partitions, with D: used for multimedia, reference materials and VMs, and E: reserved for longer term storage, including software libraries and backup images.
On my working laptop, I have the same sized C: partition, roughly mirroring my desktop C: drive, and a single data partition, where the essential folder trees from the two data partitions on the desktop are mirrored.
Keeping the C: partitions small allows me to image them regularly, while most of what is on the data drives is backed up on external drives.
Earlier this year, I added 120GB SSDs to both desktop and laptop and moved C: to them while keeping the hard drives for the data partitions. This was possible on the laptop because it has an mSata slot, and on the desktop by wedging a 2.5" bracket into space under its single drive cage.
The difference was more dramatic than I had expected and after a couple of months, I have become a believer in using an SSD for one's system drive. If you spend a lot of time in front of a computer, it makes day-to-day work much more pleasant: Programs load almost instantaneously and, perhaps surprisingly, browsing is also faster and smoother, which I attribute to the browser's caching to the SSD.