Six-time FA Cup winners Liverpool play Manchester United, who have lifted the famous trophy on 11 occasions, in the showpiece tie of the fifth round draw.
League One side Brentford, who knocked out Premiership side Sunderland at the weekend, have a chance to add another top-flight scalp to their tally having been given an away tie at Charlton.
Colchester, the only other team from outside the top two divisions left in the competition, probably face an even tougher task as they must travel to meet the winners of Everton and Chelsea.
There are two other all-Premiership clashes, with Aston Villa hosting Manchester City and Bolton, conquerors of holders Arsenal, taking on West Ham at the Reebok Stadium.
Newcastle play Southampton at home, the winners of the replay between Birmingham and Reading will travel to Coca-Cola Championship side Stoke while if Middlesbrough come through their replay at home to Coventry they are on the road again, this time to Preston or Crystal Palace.
The full draw:
Preston or Crystal Palace v Coventry or Middlesbrough
Newcastle Utd v Southampton
Aston Villa v Manchester City
Everton or Chelsea v Colchester
Charlton v Brentford
Liverpool v Man Utd
Bolton v West Ham
Stoke v Reading or Birmingham
Ties to be played weekend of February 18/19