Liverpool v Manchester United
Liverpool and United clash on Saturday in a hugely anticipated meeting at Anfield of the two most successful sides in English football history.
Sir Alex Ferguson is without Phil Jones, Rio Ferdinand and Nani as the injuries stack up at Old Traffrord, while Wayne Rooney faces a late fitness test.
With injuries also afflicting midfielder, Ryan Giggs and Paul Scholes could start alongside each other in central midfielder - at a combined age of 75.
Craig Bellamy could feature for Liverpool considering his recent impressive form, while Andy Carroll looks set to start after being rested in midweek.
QPR v Chelsea
The West London rivals meet in the FA Cup for the first time since the John Terry race row that overshadowed the last fixture between the two back in October.
Terry and Anton Ferdinand will almost certainly start, while Nedum Ohuhua and Gary Cahill could make their debuts in what looks certain to be a fiery clash.
Brighton & Hove Albion v Newcastle
There are 16 other teams in action on Saturday, including Newcastle United who are facing a tricky tie at Championship side Brighton & Hove Albion.
Arsenal v Aston Villa
With Arsenal suffering 3 Barclays Premier League defeats in a row, progress to the 5th Round of the FA Cup would give the Gunners a much needed boost.
Mikel Arteta and Thierry Henry return, while youngster Alex Oxlade-Chamberlain will likely start after his impressive display against the Red Devils last weekend.
Sunderland v Middlesbrough
Also on Sunday, Martin O Neill faces his first North East derby as Sunderland welcoming Championship high flyers Middlesbrough to the Stadium of Light.