It depends on what you are using the system for.
(Says me with 50+ computers...
)
Any CDROM, DVD, USB key, etc, can only take one letter, and it just depends on how many you want.
Partitioning up a HD can be questionable. Depends on your budget, IDE slots, etc.
Performance? One partition to the drive. Possibly multiple drives to the partition. (Can you say RAID?)
Experiment: Try copying a file from one drive letter to the other.
Results:
1. Two hard drives, very fast.
2. One hard drive, two partitions, much slower.
You get killed by the head seek from one partition to the other.
If you aren't backing up your data, you didn't want it anyway. Backup does not have to be a "backup" device. Could just be a second HD. Or CDR, DVDR, etc.
Disk drives are cheap enough now, that not backing up to another drive is, umm, not so smart.
Disk drives are cheap enough that tape drive manufacturers are in trouble. A 200G LTO tape drive costs more than 10 times the space in HDs.
Plus tapes.