Holders Liverpool take on familiar FA Cup foes Arsenal while Paul Ince's Macclesfield Town are hoping for a spot of giant-killing at Chelsea when the third round gets underway this weekend.
Liverpool's match on Saturday is one of four all-Premier League tussles, with leaders Manchester United also hosting Aston Villa, Everton taking on Blackburn Rovers and Portsmouth facing Wigan Athletic.
For Liverpool fans, the match at Anfield will rekindle happy memories of the first FA Cup final hosted by Cardiff in 2001 when two late goals by Michael Owen earned a 2-1 win over Arsenal.
Arsenal gained revenge the following season by knocking the Anfield club out in the fourth round but recent form suggests Arsene Wenger's erratic side are underdogs on Saturday.
Anfield has become a fortress for Rafael Benitez's men, with Monday's 3-0 victory over Bolton Wanderers making it nine wins and two draws in 11 home league games this season. Their last home league defeat came in October 2005.
Arsenal, with five league defeats on the road, including last weekend's humbling at Sheffield United, look a far cry from the team who beat Liverpool 3-0 at the Emirates Stadium in November.
Winners over Manchester United on penalties in the 2005 final, earning Wenger a fourth FA Cup, Arsenal were relieved skipper Thierry Henry made a scoring return in Tuesday's 4-0 league win over Charlton Athletic.
Adding further spice to the tie is that the two sides are chasing a Champions League place next season and will meet on Merseyside again on Tuesday in a League Cup quarter-final.
Supporters of fourth division Macclesfield will be dreaming of adding to the romance of a competition founded in 1871 when they take on league champions Chelsea at Stamford Bridge on Saturday.
Macclesfield have already enjoyed a fairytale run since former England and Manchester United midfielder Ince took over in October, when they were without a win and bottom of the 92-club pile in English soccer.
Though they lost his first game in charge, they have been beaten only once in 13 games since and have won seven of their last eight in all competitions.
Ince, who at 39 is considering whether to pick himself, possibly as a late substitute, is realistic about their chances.
"We don't expect to win," he told The Independent last weekend. "Macclesfield are never going to win the FA Cup so that's not on my list of priorities.
"My priority is to stay in this league. For us it's a great chance for the lads to go and play against world-class players and enjoy the sights of London...I don't think some of them have even been to London before."
Minor league Tamworth, who also reached the third round last season, will look to upset the form book against second division Norwich City.
Third division Brighton & Hove Albion must also fancy their chances at last season's beaten finalists West Ham United, crushed 6-0 by Reading on Monday to remain in the Premier League's bottom three.
Manchester United, who have won the trophy a record 11 times, will need to find a way past an obdurate Villa defence at Old Trafford on Sunday.