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.
9. Cobblers 1 Fulham 0 - League Cup
August 22, 2000 - Town beat second tier Fulham 1-0 thanks to a Marco Gabbiadini strike, but were thumped 4-1 in the second leg at Craven Cottage. Town played the same team in 1999 as well, losing 2-1 at home and 3-1 away | Getty Photo: Pete Norton
10. Cobblers 1 Tottenham Hotspur 3 - League Cup
October 27, 1998 - Town led through a Sean Parrish goal, but Spurs hit back to win thanks to efforts from Chris Armstrong (2) and Sol Campbell | Getty Photo: Pete Norton
11. Cobblers 2 West Ham United 0 - League Cup
September 15, 1998 - Premier League Hammers were beaten thanks to a Chris Freestone double. Town lost the second 1-0 at Upton Park, but progressed on aggregate | Getty Photo: Pete Norton