Norwich City and Queens Park Rangers joined Aston Villa on the FA Cup scrapheap after famous wins for non-league Luton Town and third-tier Milton Keynes Dons in the fourth round on Saturday.
Luton, of the fifth-tier Conference National, won 1-0 at Norwich through an 80th-minute Scott Rendell goal to become the first non-league team to eliminate top-flight opposition in 24 years.
League Cup winners in 1988 but relegated from the Football League after going into administration in 2009, Luton began the day 85 places below their opponents in the English league pyramid.
They will be only the seventh non-league team to compete in the fifth round since World War II.
"It's a lot to take in," said Luton manager Paul Buckle.
"The players were tremendous today. They held a Premier League team for 90-plus minutes."
It was also an emotional return to his hometown club for Mark Tyler.
The Hatters goalkeeper, who was a Norwich fan as a boy and played in their youth academy, made a string of top saves.
"This is where I started my career, this is where I wanted to play as a young boy, so to come back here and keep a clean sheet means the absolute world to them and my family."
QPR, the Premier League's bottom club, will be able to focus all their efforts on avoiding relegation after a humiliating 4-2 defeat at home to MK Dons of League One.
Although QPR manager Harry Redknapp made nine changes to his team, his starting XI still featured seven full internationals, but they fell behind in the fourth minute when Armand Traore put through his own goal.
Strikes from Ryan Lowe, Ryan Harley and Darren Potter put the visitors 4-0 up by the 56th minute, before Jay Bothroyd and Fabio da Silva claimed a pair of consolation goals for QPR.
Redknapp tore into his players after the game.
"If you look at the team today, what is it? An England goalkeeper (Rob Green), a right-back from Man United (Fabio), a left-back in Armand Traore," Redknapp said.
"You've got Anton Ferdinand and Tal Ben Haim, then Esteban Granero from Real Madrid. You've got Ale Faurlin, Park Ji-sung from Man United, Jamie Mackie, Jay Bothroyd and DJ Campbell.
"Surely they are entitled to beat a team from two divisions down? It tells me, like I've said all along, that I need to improve the squad."
Premier League leaders Manchester United enjoyed a much more straightforward fourth-round assignment, sweeping past Fulham 4-1 at Old Trafford to reach the fifth round with ease.
Veteran midfielder Ryan Giggs gave United the lead in the third minute, planting a penalty in the bottom-left corner after Aaron Hughes had been penalised for handball.
United stepped up the pace early in the second period, with Wayne Rooney claiming a neatly taken goal in the 50th minute before a quick-fire Javier Hernandez double put the game to bed.
Hughes replied with a 77th-minute header for Fulham, who welcome United to Craven Cottage in the league next weekend.
"It means a lot, as we've not done as well as we should have (in the FA Cup) in the last eight or nine years," Giggs told ESPN.
"There are a lot of players desperate to win it. With the history we've got in the competition, we should be getting to finals, so hopefully this will the year."
Arsenal needed a late Theo Walcott goal to record a 3-2 win at second-tier Brighton and Hove Albion, conquerors of Newcastle United in the previous round.
Olivier Giroud twice gave Arsenal the lead, taking his tally to four goals in two games, but Brighton hit back to equalise on each occasion through headers from Ashley Barnes and Argentine debutant Leonardo Ulloa.
Arsenal had the last word, however, with Walcott netting in the 85th minute to spare Arsene Wenger's men the inconvenience of a replay.
Everton, fifth in the Premier League, also had a narrow escape against second-tier opposition and needed an injury-time winner from John Heitinga to prevail 2-1 at Bolton Wanderers.
Macclesfield Town were unable to match the exploits of fifth-tier rivals Luton, going down 1-0 at home to Wigan Athletic courtesy of a seventh-minute Jordi Gomez penalty.
Earlier, a late goal by Pablo Zabaleta earned Manchester City a 1-0 win in an attritional tie at bogey team Stoke City.
The English champions had not won at Stoke in six previous visits and they lost captain and centre-back Vincent Kompany to a calf injury in the first half.
However, Zabaleta struck in the 85th minute to send Roberto Mancini's men into round five, finishing deftly from Sergio Aguero's low cross to complete a move that he had started.
"Today we were solid at the back, and up front we were very aggressive," said Zabaleta, an FA Cup winner with City in 2011, when they beat Stoke.
"The Stoke crowd push the team a lot and we knew it was going to be difficult for us. We want to win the FA Cup again."
The fourth round had opened with an upset on Friday when Villa, beaten by fourth-tier Bradford City in the League Cup semi-finals in mid-week, lost 2-1 at Championship club Millwall.