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.
1. Cobblers 2 MK Dons 2 - FA Cup
January 9, 2016 - MK were a Championship side when they arrived at Sixfields, and needed a late equaliser to set up a reply (which Town lost). Both of Town's goals were scored by Ricky Holmes | Getty Photo: Pete Norton
2. Cobblers 1 Wolves 3 - League Cup
August 30, 2012 - Clive Platt netted for the Cobblers, but they were well beaten by Championship side Wolves, who were relegated to league one at the end of the season | Getty Photo: Pete Norton
3. Cobblers 2 Cardiff City 1 - League Cup
August 14, 2012 - Town came from behind to beat Cardiff thanks to goals from David Artell and Alex Nicholls. The Bluebirds would be promoted to the Premier League that season | Getty Photo: Pete Norton
4. Cobblers 3 Queens Park Rangers 0 - League Cup
August 23, 2005 - Ian Holloway's Championship side QPR were swept aside thanks to goals from Andy Kirk, Scott McGleish and Eric Sabin | Getty Photo: Pete Norton