Will Grigg scored twice to become the FA Cup's leading goalscorer as Wigan Athletic collected another Premier League scalp, dumping 10-man West Ham United out of the competition on Sunday (AEDT).
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 has shown improvement under new coach Carlos Carvalhal but was 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.
Wigan is no stranger 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 is full of confidence and took just seven minutes to take the lead at 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 its place in the fifth round via another Grigg goal, the Northern Ireland international converting a penalty awarded for a handball by Reece Burke.
Although Swansea City remains bottom of the Premier League, Carvalhal had overseen victories in its past two matches, including a win against Liverpool, ahead of Sunday's (AEDT) cup trip to Notts County.
Remarkably, the League Two promotion contender, 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.
Joining fellow League Two side County in the fifth-round draw is Coventry City, which 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's men through against their League One host.
Rochdale is in danger of slipping into League Two but 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's 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.
After conquering holder 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.
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, 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 it drew 1-1 at home to Championship side Birmingham City, with Lukas Jutkiewicz scoring in his fourth straight FA Cup start.