Luton Town made FA Cup history with a 1-0 win away to Norwich City at Carrow Road, becoming the first non-league side in 27 years to beat a Premier League side away from home.
Substitute Scott Rendell scored from close range 10 minutes from time to seal a famous win over a Premier League team ranked 85 places above them in the league ladder.
Rendell drifted to the near post and poked the ball into the net to convert JJ O'Donnell's cross to cap off a brilliant performance from the Conference National side.
Norwich boss Chris Hughton rested several players, but as Luton - in particular goalkeeper Mark Tyler - held firm, club captain Grant Holt was deployed from the substitutes' bench at half-time.
Holt brought a great save from Tyler with a diving header, and soon after Anthony Pilkington and Wes Hoolahan also came on as Norwich pushed for the win.
But then came Luton's sucker punch - Alex Lawless had just volleyed wide when O'Donnell got free down the left, and Rendell showed great desire to beat the defenders to the ball and complete an FA Cup miracle.
At Loftus Road there was a result every bit as extraordinary as MK Dons destroyed QPR 4-2 on an afternoon that saw two of the most extraordinary FA Cup upsets of recent years.
QPR's woes began when Armand Traore scored an own goal after just four minutes to put the League One side in front against their Premier League hosts.
Ryan Lowe then doubled the lead before the break, with Ryan Harley and Darren Potter adding two more goals in the first 10 minutes of the second half.
QPR tried to fight back and Jay Bothroyd and Fabio both scored in the last seven minutes, but the Dons held on to consign Harry Redknapp's beleaguered side to yet another humiliating afternoon.
Another top flight club, Wigan Athletic, survived a scare against non-league Macclesfield Town as they won 1-0, but the visitors were forced to hang on to their slender lead for 83 minutes following Jordi Gomez's early penalty.
Top flight Reading had no such trouble against League One side Sheffield United, with two goals by Noel Hunt and one apiece from Garath McCleary and Mikele Leigertwood wrapping a 4-0 win up before the hour mark.
Everton struck deep in injury time to earn a 2-1 win over Championship side Bolton Wanderers. Steven Pienaar opened the scoring for the Toffees on 18 minutes before Marvin Sordell popped up ten minutes later with a goal that looked like securing a replay for Dougie Freedman's men, only for Johnny Heitinga to find the net in the dying moments.
There was also late drama as League Two Aldershot Town almost enjoyed a superb afternoon as they lost 2-1 to Championship side Middlesbrough. Boro had appeared to pinch it on 83 minutes as Lukas Jutkiewicz struck, but Danny Hylton then seemed to have earned Aldershot a replay with his injury time goal.
Yet there was still time left, and Jutkiewicz scored again to earn Boro passage into the fifth round.
Huddersfield and Leicester City will also meet again after Chris Wood popped up eight minutes from time for the Foxes to cancel out Lee Novak's penalty and secure a 1-1 draw.
Blackburn Rovers cruised into the fifth round with a 3-0 demolition job away at Derby County, with Colin Kazim-Richards, Scott Dann and Jordan Rhodes all on target, while Barnsley also made it through with a 70th minute goal by Chris Dagnall giving them a 1-0 win over Championship high-fliers Hull City.
Earlier, Pablo Zabaleta's goal just five minutes from time earned Manchester City an FA Cup fourth-round victory over Stoke Saturday evening.
The win advanced Manchester City into the fifth round of the Football Association's major competition - and set Stoke down.
The Argentine's smart low finish was a rare moment of quality in an otherwise limp Cup tie that was watched by fewer than 20,000 despite the hosts offering discounted tickets at Stoke's Britannia Stadium.