Will Grigg scored twice to become the FA Cup's leading goalscorer as Wigan Athletic collected another Premier League scalp, dumping out 10-man West Ham United on Saturday.
Grigg took his tally to six goals in this season's competition as Wigan followed up a third-round success over Bournemouth with another victory over top-flight opposition.
Swansea City have shown improvement under their new coach Carlos Carvalhal but were held at Notts County.
League Two side Coventry City booked a place in the fifth round with a win at MK Dons, while Javi Gracia's first game in charge of Watford ended in defeat.
2013 CHAMPIONS MARCH ON
Wigan are no strangers to cup shocks, of course, having triumphed against the odds to beat Manchester City in the 2013 final, although Roberto Martinez's men were relegated from the Premier League in the same season.
Top of League One, Wigan are full of confidence and they took just seven minutes to take the lead at the DW Stadium, Grigg on target from Nathan Byrne's assist.
West Ham's chances of launching a second-half fightback were hit when Arthur Masuaku was sent-off shortly after the restart, the left-back dismissed after spitting at Nick Powell, David Moyes condemning the player's "despicable" actions.
Wigan secured their place in the fifth round via another Grigg goal, the Northern Ireland international converting a penalty awarded for a handball by Reece Burke.
SWANSEA MOMENTUM HALTED
Although Swansea City remain bottom of the Premier League, Carvalhal had overseen victories in their last two matches - including a win against Liverpool - ahead of Saturday's trip to Notts County.
Remarkably, the League Two promotion contenders - led by Kevin Nolan - named a starting XI with a combined number of Premier League appearances of 517, more than the 468 in the Swansea team.
After Renato Sanches was forced off through injury, Swansea took the lead on the stroke of half-time with a goal from Luciano Narsingh.
But one of County's former Premier League players came up with the equaliser, Jon Stead turning home from close range to keep up his run of scoring in every round of this season's FA Cup.
COVENTRY UPSET MK DONS
Joining fellow League Two side County in the fifth-round draw are Coventry City, who won 1-0 at MK Dons.
Max Biamou scored the only goal of the game, knocking home a Jack Grimmer cross to send Mark Robins' men through against their League One hosts.
Rochdale are in danger of slipping into League Two but they earned a replay at home after a 2-2 draw at Championship side Millwall.
Ben Thompson struck late for the Lions to keep Neil Harris' men in the competition after goals from Ian Henderson and Matt Done had helped Dale come from behind.
The all-Championship tie between Sheffield United and Preston North End saw the Blades edge through 1-0, Billy Sharp scoring the winner with 10 minutes to go.
And after conquering holders Arsenal in the last round, Nottingham Forest went out with a 2-1 loss at fellow Championship side Hull City, Jarrod Bowen scoring and providing an assist for Nouha Dicko.
GRACIA STARTS WITH A DEFEAT
Watford wasted no time in appointing Javi Gracia as the successor to the sacked Marco Silva, but the Spaniard's reign started with an FA Cup defeat at the hands of Southampton.
Birthday boy Jack Stephens finished off a rebound after Shane Long was denied to book a fifth-round place for beleagured boss Mauricio Pellegrino.
Earlier on Saturday, Leicester City thumped Peterborough United 5-1 with Kelechi Iheanacho scoring a brace for the second round in a row, while Fousseni Diabate also netted twice on his Foxes debut.
Glenn Murray's late goal secured Brighton and Hove Albion a derby win against Crystal Palace in the third round and the striker was at it again, coming off the bench to down Middlesbrough 1-0.
Huddersfield Town, however, will need a replay after they drew 1-1 at home to Birmingham City of the Championship, with Lukas Jutkiewicz scoring in his fourth straight FA Cup start.