Sunderland suffered an embarrassing League Cup second round exit as Roy Keane's side lost 3-0 at Luton on Tuesday.
Keane enjoyed many Cup triumphs during his playing career, but the former Manchester United star was on the receiving end of a giant-killing at Kenilworth Road.
David Bell and Paul Furlong were the heroes for League One Luton, who made a mockery of the two-division gap between the clubs.
The defeat will be even more galling to Keane as, unlike many of his Premier League counterparts, he had treated the competition with respect.
Sunderland had clinched the championship title at Luton last season, but their misery was complete when Greg Halford was sent off for a second booking and Furlong put the icing on the cake for Luton in the 75th minute.
Wigan were another Premier League casualty as Hull winger Stuart Elliott's first-half goal gave the championship team a 1-0 win at the JJB Stadium.
Latics manager Chris Hutchings made nine changes and paid the price as Andreas Granqvist's error settled the tie.
The Sweden defender made a hash of his clearance and Elliott pounced to grab the only goal in the 31st minute.
Derby twice blew the chance to kill off Blackpool and suffered the consequences as the Premier League team lost 7-6 on penalties after a 2-2 draw.
Mo Camara opened the scoring for Billy Davies's side before Kaspars Gorkss equalized with four minutes to play. Fagan restored the Rams' lead in the 101st minute, but Gorkss levelled again for the Championship outfit in the last minute of extra-time.
Craig Bellamy's double strike eased West Ham to a 2-1 win at League One Bristol Rovers, but the result was marred by a serious injury to Kieron Dyer.
England midfielder Dyer faces a lengthy spell on the sidelines after reportedly breaking two bones in his leg in a tackle with Joe Jacobson early in the match.
Rovers pulled one back through Andrew Williams in the 72nd minute but it was too little, too late.
Shaun Maloney scored twice as Aston Villa cruised through with a 5-0 win at League Two Wrexham.
Scottish striker Maloney broke the deadlock in the 30th minute. Luke Moore and Nigel Reo-Coker got on the scoresheet in the second half before Maloney added his second and Marlon Harewood grabbed the fifth.
Birmingham manager Steve Bruce made seven changes against Hereford, but Garry O'Connor and Gary McSheffrey's first half goals secured a 2-1 win at St Andrews.
David Nugent got his first Portsmouth goal as Harry Redknapp's side ended Leeds' perfect start to the season with a 3-0 win.
Ten-man Reading needed extra time before finally beating League One Swansea 1-0.
Sam Sodje was sent off for Steve Coppell's Premier League team after an hour, but Leroy Lita got the winner in the 105th minute.
Diomany Kamara's second half goal gave Fulham a 1-0 win at Shrewsbury, while League Two Morecambe shocked Wolverhampton 3-1 after extra-time.
Leicester's tie at Nottingham Forest was abandoned after Clive Clarke collapsed in the dressing room at half-time.