I really haven't taken the time it test for the optimum. The way I set it up is that I leave the OS drive at the default size. (Windows has a bat-**** heavy load of tiny little files.)
My drives for disc rips, digital photos, HD home videos, and DVRed TV shows all get formatted at 64K size.
My main backup drive, which is used for prompt backups of photos & home videos, as well a general catch all for downloaded programs, updates, etc.; I format at 32K. The external USB HDDs that are used less often for offline backup are formatted at the default size.
I'll normally defrag the OS drive right after a fresh install of the OS and all programs, but otherwise I don't really defrag anything.
The only time I've seen large cluster sizes make a definite difference (the difference between working and not working) is with DVRing multiple HD tuners. But the little bit faster advantage is a plus with ripping as well as general photo editing, imo. The Gig or so of space lost (absolute worst case) in my setup is worth it to me.
-Suntan