I have three HDs. C: is for Windows, D: is for the data drive (all emulators and their configs), and E: is a backup of D: (and a few select folders on C:). I don't backup all of C: since I generally consider a system hard drive failure to be an "opportunity" to clean up my system and update my OS :-) Losing D: however, would be truly nasty.
To backup I use an AHK script that calls Robocopy.exe with its /mir option on each top level folder I need backed up. The backup goes to E:. I run this with a hotkey periodically as needed. Robocopy.exe is built into most newer versions of Windows and is able to mirror arbitrarily deep directories extremely fast (it only copies deltas). Backups are just ordinary folders, so restore is easy. For example, if D: fails, simply renaming E: as D: will put me back in business.