Backup Server software

We are interested in the backup server software.
We have a 2003 server (domain Controller, dns, dhcp)

We want a backup that will backup up everything, so that we can retrieve files if need be but also the whole system in case of total failure. (so new computer).

We have been using ntbackup to this point.

Currently we do a (full) normal backup once a week then follow up the rest of the week with differential backups. We have two hard drives that we swap out each week and put one in a safe. (the hard drives we back up are small 35 gig each)

The secretary does this (swapping of the drives) The backup is on a scedule at night. Sometimes she does it on monday but sometimes forgets to do it for several days. (or is busy).

My question is : If the secretary swaps out the drive mid week. after a full backup has been done (say its done on Sat) and she takes the drive out on wed. Is that going to mess with the program. and confuse it as far as which is the latest files. Im guessing it just uses the archive bit to backup the diff files.

On a restore can you restore the drive, then restore the differential backup from which ever USB drive has the latest files?

Perhaps Im not explaining it well, but do you understand what I mean?
Thanks.