Liverpool suffered one of the biggest shocks in FA Cup history as they were humbled 1-2 at home by Barnsley in the fifth round.
Brian Howard slammed in the winner in injury time Saturday as Barnsley came from behind to stun Rafael Benitez's side.
Manchester United thrashed Arsenal 4-0 and Chelsea survived a few tense moments before beating Huddersfield 3-1, while West Bromwich Albion and Cardiff City also booked their places in the quarter-finals.
But the real drama came at Anfield where Barnsley, stuck in the bottom half of the Premiership, came from behind to beat Liverpool in a monumental upset.
Liverpool left out Fernando Torres as he recovers from injury while Steven Gerrard began on the bench but things looked normal as Dirk Kuyt put them ahead just after the hour mark.
But the match turned 10 minutes after half-time when Stephen Foster headed them level after an excellent cross by Martin Devaney. Liverpool brought Gerrard on to find the winner but Harry Kewell hit the crossbar and Luke Steele pulled off a series of superb saves to keep them out.
Just when it looked like a replay, Howard smashed home a shot from 20 yards to send the visiting fans wild and leave Liverpool shell-shocked.
Liverpool manager Benitez was shocked and said: "Frankly I am stunned and bitterly frustrated. The team is very upset. But we made so many chances and their keeper was the man of the match. I lost count of the times the ball was kicked off their line."
"We were ahead at the break and should have got a killer second goal. It is difficult to explain how we do not score from so many opportunities. You cannot blame any one player, but now we have to look to the next game against Inter (Milan, in the Champions League). We cannot change anything now about Barnsley, we have to concentrate on putting things right in the next match," he added.
In the other match, United allowed themselves the luxury of leaving out Cristiano Ronaldo altogether for the visit of Arsenal, though Wayne Rooney returned from suspension.
And the match was as good as over by half-time, as Rooney, Darren Fletcher and Nani put them 3-0 ahead.
Arsenal's Emmanuel Eboue was sent off shortly after the break, and second half turned into a cakewalk for United. Fletcher put the seal on the win with the fourth 16 minutes from time.
Chelsea looked set for a struggle when Huddersfield's Michael Collins equalised Frank Lampard's early goal at Stamford Bridge. But Lampard made it 2-1 and Salomon Kalou sealed their 3-1 victory. Roman Bednar scored twice as West Brom won 5-0 at Coventry City while early goals from Peter Whittinghm and Jimmy Floyd Hasselbaink gave Cardiff City a 2-0 win over Wolves.
Bristol Rovers upset Southampton 1-0 in the day's other match.