Arsenal and Manchester City take a break from their battle at the top of the Premier League to try and remain on course for a quadruple this weekend as Wigan and Salford seek monumental FA Cup shocks.
Aston Villa and Newcastle are aiming to end their seven-decade waits for FA Cup glory when they face off in the tie of the round.
Sixth-tier Macclesfield produced arguably the biggest ever upset in the competition's history by knocking out holders Crystal Palace in the last round and have another Premier League scalp in their sights against Brentford.
AFP Sport looks at three of the talking points ahead of fourth round weekend:
ARSENAL, CITY ON COURSE FOR UNPRECEDENTED QUADRUPLE
City have already matched the greatest season in English football history three years ago by joining Manchester United's class of 1998/99 in winning the Champions League, Premier League and FA Cup in the same season.
But no side has ever won all three of those titles plus the League Cup.
Arsenal and City will face off for the first silverware of the season next month and the unprecedented quadruple remains on for both clubs.
The Gunners hold a four-point lead over Pep Guardiola's men at the top of the Premier League, but City have home advantage when the sides meet in April.
Both also progressed directly to the last 16 of the Champions League.
And it would be a huge surprise if they are not in the hat for found five on Monday.
The Gunners host Wigan, winners of the FA Cup in 2013, who currently sit in the League One relegation zone.
Fourth-tier Salford, co-owned by United legends David Beckham and Gary Neville, head to the Etihad hoping to avoid a repeat of the 8-0 thrashing they suffered at the hands of City last season.
CAN VILLA END TROPHY DROUGHT?
Villa are the best of the rest behind the Premier League's top two, but with winning the title now a distant dream, Unai Emery's men are aiming to end a 30-year wait to win a major trophy.
Villa's last FA Cup success was back in 1957, two years after Newcastle last lifted the trophy.
The Magpies ended their 70-year drought for domestic silverware by winning the League Cup last season.
Sitting 10th in the Premier League, Eddie Howe's side may need FA Cup glory to salvage an otherwise disappointing campaign.
However, Newcastle have struggled on the road all season and are likely to be without influential captain Bruno Guimaraes due to a hamstring injury.
MACCLESFIELD SEEK ANOTHER 'MIRACLE'
The 117 places that separated Nations League North Macclesfield from Palace was the biggest gap ever overcome by the underdog in FA Cup history.
But they could break their own record on Monday when Brentford, who sit seventh in the top flight, visit Moss Rose.
"We went into the Crystal Palace game thinking it would take a miracle, but on the day the lads were outstanding and were fully-deserved winners," said Macclesfield boss John Rooney, the brother of former England and Manchester United captain Wayne Rooney.
"There will be a lot more eyes on us, expecting an upset, but that's testament to the club, to the players, to the staff, everyone who made the day possible."
FIXTURES
Friday (all times GMT)
Hull v Chelsea, Wrexham v Ipswich (both 19:45)
Saturday
Burton v West Ham (12:15), Burnley v Mansfield, Norwich v West Brom, Manchester City v Salford, Southampton v Leicester, Port Vale v Bristol City (all 15:00), Aston Villa v Newcastle (17:45), Liverpool v Brighton (20:00)
Sunday
Birmingham v Leeds (12:00), Grimsby v Wolves (1330), Stoke v Fulham, Oxford v Sunderland (14:00), Arsenal v Wigan (16:30)
Monday
Macclesfield v Brentford (19:30)