Non-league Luton Town stunned Norwich City to reach the fifth round of the FA Cup and MK Dons shocked Queens Park Rangers at Loftus Road.
Macclesfield Town battled bravely before bowing out to top-flight Wigan Athletic and Aldershot Town were denied a replay against Middlesbrough by a last-minute winner.
Arsenal and Everton overcame Championship opponents away from home, Reading cruised past Sheffield United, Manchester City edged past Stoke City and Manchester United thumped Fulham.
Luton became the first non-league team to knock a top-flight club out of the FA Cup since 1989 after a memorable 1-0 victory at Norwich.
After a tight encounter at Carrow Road, the decisive goal came 10 minutes from time when Scott Rendell sent the Hatters into the fifth round.
MK Dons also pulled off an upset after a 4-2 victory at Queens Park Rangers, who scored two late goals to make the scoreline look more flattering.
Armand Traore's early own goal had set MK Dons on their way and further goals from Ryan Lowe, Ryan Harley and Darren Potter dumped the Premier League strugglers out of the competition.
There was no such slip-up for Wigan, however, as Jordi Gomez's seventh minute penalty secured a 1-0 win at Conference club Macclesfield.
Reading also ensured there was no upset as Brian McDermott's side ran out convincing 4-0 winners over Sheffield United at the Madejski Stadium.
Noel Hunt scored a goal in each half, Mikele Leigertwood netted against his former club and Garath McCleary was also on target for the Royals.
Lukas Jutkiewicz scored deep into stoppage-time as Middlesbrough broke Aldershot hearts thanks to a 2-1 win at The Riverside.
Arsenal twice threw away the lead at Brighton before Theo Walcott's 85th minute goal secured a 3-2 success at the AMEX Stadium.
Olivier Giroud scored a goal in each half for Arsenal, but Brighton drew level on each occasion through Ashley Barnes and debutant Jose Ulloa before Walcott spared the Gunners the need for a replay.
Johnny Heitinga scored a last-minute winner as Everton advanced to the last 16 courtesy of a 2-1 win at Bolton Wanderers.
Steven Pienaar's 18th minute opener had been cancelled out by the in-form Marvin Sordell before Heitinga popped up in the last minute to send Everton through.
Manchester United had little trouble making it through to the fifth round following a 4-1 victory over Fulham at Old Trafford.
Ryan Giggs' early penalty following an Aaron Hughes handball got United up and running before Wayne Rooney's goal was added to by a Javier Hernandez brace.
Stoke failed to avenge a 2011 FA Cup final defeat by Manchester City after Pablo Zabaleta's late strike earned the Premier League champions a 1-0 win at the Britannia Stadium.
Zabaleta flicked home with the outside of his boot five minutes from time, while Stoke midfielder Glenn Whelan was fortunate not to be sent off for a challenge on Javi Garcia early in the second half.
Chris Wood continued his impressive strike-rate since joining Leicester City by scoring an 82nd minute equaliser in a 1-1 draw at managerless Huddersfield Town.
Barnsley made it through to the fifth round at Hull City's expense after Chris Dagnall's goal 20 minutes from time earned a 1-0 win at the KC Stadium.
In another all-Championship tie, Blackburn Rovers eased through, with Jordan Rhodes among the scorers in a 3-0 win at Derby County.