Luton claimed the biggest scalp of the day as they claimed a shock win at Norwich, while QPR can fully focus their attentions on their battle for Premier League survival after they were dumped out of the FA Cup by League One side MK Dons.
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• Blog: Norwich's day of ignominy
• Millwall 2-1 Aston Villa
Meanwhile, Arsenal and Manchester City both scraped through after narrow victories, while Everton snatched a late win to sink Bolton.
Luton Town became the first non-league side in 24 years to beat top-flight opposition as the Conference outfit defeated Norwich 1-0 at Carrow Road thanks to Scott Rendell's late finish.
The Hatters were preoccupied with defending for much of the contest, but substitute Rendell stunned the top-flight opponents with just ten minutes remaining as he found himself in the right place at the right time to steer home JJ O'Donnell's low cross.
Canaries boss Chris Hughton perhaps paid the price for starting the ineffective Simeon Jackson and Harry Kane up front, and even Grant Holt's late introduction could not produce a breakthrough. The unheralded visitors were reasonable value for their success, though, creating a number of opportunities over the course of the contest as they also edged the possession statistics.
Where Holt's introduction did not have the desired effect, Luton manager Paul Buckle's tactical change certainly did. Rendell had been on the pitch just six minutes when he scored the historic winner, blasting past Declan Rudd to write his name into cup folklore.
Relegation-threatened QPR suffered major embarrassment as they were beaten 4-2 by League One promotion contenders Milton Keynes Dons.
Rangers manager Harry Redknapp could have been forgiven for fearing that things were not going to go his side's way early on after Armand Traore deflected a low cross - that had perhaps first been touched on by Dean Lewington - beyond goalkeeper Robert Green and into his own net.
Things got worse for Redknapp's rotated side as a poor mistake from Anton Ferdinand allowed Ryan Lowe in behind the defence to make it 2-0 shortly before half-time. Ryan Harley and Darren Potter then scored similar close-range strikes six minutes apart to leave the West London club, somewhat shamefully, four goals adrift in front of their own fans.
The scoreline was not entirely representative of the full 90 minutes' play but QPR only made something of their great number of chances in the closing stages, as Jay Bothroyd latched onto Bobby Zamora's flick on to get on the scoresheet, having already been guilty of a number of misses earlier in the contest.
Pablo Zabaleta scored in the 85th minute to send Manchester City into the fifth round with a 1-0 victory over Stoke.
In a repeat of the 2011 final, when City also won 1-0, the Premier League champions dominated the action primarily through the dual threats of Carlos Tevez and David Silva, although Stoke had a goal from Ryan Shawcross ruled out for offside.
City finally broke through five minutes from time when Silva's late break forward gave Sergio Aguero the chance to play the ball across the area, and Zabaleta arrived at the back post to turn it goalwards.
Olivier Giroud bagged a brace as Arsenal moved into the last 16 with a 3-2 victory at Brighton & Hove Albion. After a rampant victory over West Ham in midweek, sloppy defending nearly cost the Gunners victory, but Theo Walcott came off the bench to seal victory.
After an end-to-end start at the Amex Stadium, Giroud fired the Gunners ahead in the 16th minute, curling the ball past Casper Ankergren from the edge of the penalty box, before Ashley Barnes levelled with a header after some poor marking.
Arsenal took the lead once again when Giroud scored his fourth goal in two games, showing real poise to hold off Adam El-Abd to finish from close range, but their lead was shortlived as Brighton hit back through Leonardo Ulloa, who marked his debut with an impressive diving header to divert Barnes' cross into the net.
Desperate to avoid a replay, Arsene Wenger brought on Jack Wilshere and Walcott, and it was the latter who snatched a late winner, his deflected volley from the edge of the area finding its way into the net.
Wayne Rooney was stripped of penalty-taking duties by Manchester United but found the net anyway as they sauntered past Fulham 4-1 to book an FA Cup fifth-round place.
After his latest miss, Rooney was passed over in favour of Ryan Giggs to take United's third-minute spot-kick. And, 20 years and three days after his first FA Cup goal, Giggs scored his 12th.
Rooney did not come alive until after the restart but once he had brutally fired home his 10th goal of the season, he quickly set up strike partner Javier Hernandez for the Mexican's 13th.
Hernandez bagged another before Aaron Hughes' consolation, ensuring Robin van Persie could remain on the bench throughout.
John Heitinga came off the bench to fire Everton to a 2-1 win over Bolton at the Reebok Stadium.
The tie looked to be heading for a replay after Marvin Sordell cancelled out Steven Pienaar's opener, but Heitinga pounced on a loose ball in the penalty area to lash home from 12 yards in injury time.
Reading cruised to a 4-0 home win over League One's Sheffield United.
Noel Hunt opened the scoring for Brian McDermott's side after just six minutes, before Mikele Leigertwood's blistering long-range effort ensured the Royals entered half-time 2-0 up. A second from Hunt, and then a further goal from Garath McCleary, ensured the contest was over as a spectacle after only 54 minutes - although the Blades did at least prevent further damage occurring over a subdued final half hour of play.
Jordi Gomez's early penalty prevented an upset at Moss Rose, as Wigan Athletic escaped with a slender 1-0 victory over Conference side Macclesfield.
With a packed crowd in attendance hoping for an upset, the Premier League visitors were handed something of a gift after Thierry Audel brought down Callum McManaman in the box after barely six minutes. It was a gift Gomez was not going to pass up, burying the penalty despite goalkeeper Joe Anyon guessing the right way.
The non-leaguers enjoyed the majority of the play for the rest of the game but were unable to steal a potentially lucrative replay, with Waide Fairhurst and Matthew Barnes-Homer both missing decent openings, as Audel also saw a close-range chance to make amends kept out by on-loan Atletico Madrid goalkeeper Joel Robles.
League Two side Aldershot were denied a home replay against Middlesbrough in heartbreaking fashion after forward Lukas Jutkiewicz made it 2-1 deep into injury time.
In a scarcely-believable finish at the Riverside Stadium, the Shots thought they had earned a second run at the Championship front-runners on their own turf after Daniel Hylton's 89th-minute equaliser had cancelled out Jutkiewicz's 83rd-minute breakthrough.
But they saw their dreams dashed at the death as Jutkiewicz popped up again in the sixth minute of injury time to fire a shot that hit the post and, after dribbling along the goalline for what seemed like an age, eventually rolled in to send Dean Holdsworth's men out of the competition.
Michael Appleton enjoyed his first win as Blackburn boss as Rovers moved into the fifth round with a 3-0 victory over Derby County courtesy of goals from Colin Kazim-Richards, Scott Dann and Jordan Rhodes.
Chris Wood grabbed a late goal to cancel out Lee Novak's penalty to earn a replay for Leicester City after a 1-1 draw at Huddersfield Town, while Chris Dagnall scored the only goal of the game as Barnsley beat Yorkshire rivals Hull City 1-0.
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