The match is a latest in a long line of occasions where Town have hosted clubs from the top two divisions of English football in either the FA Cup or League Cup.
Wayne Rooney's Rams arrive in Northampton as big favourites to see off League Two Cobblers, but as we all know, strange things can happen in cup competitions!
The first major cup game held at Sixfields, the Cobblers' home since October, 1994, saw Football League Division One side West Bromwich Albion come to town on August 22, 1995.
It was a League Cup first round clash, and the Baggies eased to a 4-2 victory, despite goals from Town midfield pair Chris Burns and Dean Peer.
Since that match, there have been several occasions when the Cobblers have hosted teams from England's top two divisions at Sixfields, in the two major English cup competitions.
They have enjoyed some glory days, some narrow misses, and a couple of heavy defeats, and they will be hoping Friday night's visit of Derby in the fourth round of the FA Cup will be one to remember for all the right reasons.
Here, sports editor Jeremy Casey looks back on the times when the Cobblers have attempted to be the giant killers...
All picures by Pete Norton.