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.
5. Cobblers 1 Southampton 3 - FA Cup
January 8, 2005 - Harry Redknapp's Saints were Sixfields winners. Lee Williamson's goal had Town in the hunt, but the visitors' class told as they won it through England men Kevin Phillips, Peter Crouch and Jamie Redknapp | Getty Photo: Pete Norton
6. Cobblers 1 Norwich City 0 - League Cup
August 12, 2003 - The second tier Canaries were beaten thanks to Josh Low's goal. Norwich went on to win promotion to the Premier League | Getty Photo: Pete Norton
7. Cobblers 0 Manchester United 3 - FA Cup
January 25, 2004 - Alex Ferguson's men eased past the Cobblers with little fuss. Town had reached round four by beating Championship side Rotherham in a round three replay, the first game at Sixfields ending 1-1 | Getty Photo: Pete Norton
8. Cobblers 2 Queens Park Rangers 1 - League Cup
August 21, 2001 - Ian Holloway's Rs were turned over at Sixfields. Jamie Forrester equalised in the final minute, with Paul McGregor winning it in extra-time | Getty Photo: Pete Norton