Arsenal begin their quest to become the first club since Blackburn Rovers in 1886 to win the English FA Cup three years in succession with a tough tie against Leeds United at Elland Road this Sunday.
Manchester United, record 10-times winners of the competition, visit Aston Villa in a plum third round match-up, while another glamour tie sends Liverpool to renowned giant-killers Yeovil.
Arsenal, who defeated Southampton 1-0 in last season's final to lift the trophy for the ninth time, will not want to slip up despite chasing glory on four fronts.
"We would love to make history," Arsenal manager Arsene Wenger told reporters today.
"And I believe we could have done it already. We have already been in three successive finals and the one we really deserved to win was three years ago against Liverpool when we lost.
"That was one of our biggest disappointments and it really hurt. I think that is one of the reasons we have done so well recently in this Cup because when you are frustrated and angry you come back even stronger.
"I agree that the Premiership is more important and the Champions League is also more important but we just try to win every game and see what we end up with at the end."
Wenger's side, one point behind United going into the second half of the premier league season, are also through to the last 16 of the Champions League and the League Cup semi-finals.
They have not lost to domestic opposition this season but will be wary of a Leeds side who have improved under caretaker boss Eddie Gray, despite a 3-1 reverse at Wolverhampton Wanderers on Saturday that kept them in the relegation zone.
The teams last met in the Cup in the 1996-1997 season when a goal from Rod Wallace gave Leeds a 1-0 win in a fourth-round tie at Highbury.
United's trip to Villa Park will evoke memories of the thrilling third-round encounter at the same ground in the 2001-02 season when Alex Ferguson's side came back from the dead to win.
Villa were cruising at 2-0 up before United scored three times in a five-minute spell late in the game -- including two goals from Ruud Van Nistelrooy in his first FA Cup tie -- to complete a comeback.
There are three other all-premier league clashes. Last season's beaten finalists Southampton take on Newcastle United, Birmingham City are at home to Blackburn Rovers and Manchester City entertain Leicester City.
Liverpool will need no reminding that third division Yeovil are the most famous of all FA Cup giant-killers, having beaten 20 league clubs before being promoted to the football league in 2003.
Yeovil will earn a cash windfall from the televised game and will have nothing to lose at their Huish Park home.
Liverpool captain Steven Gerrard is a major doubt for the game after suffering a thigh injury in the 2-2 draw at Manchester City on Sunday.
As ever in the world's oldest cup competition there is the potential for upsets, particularly at White Hart Lane where struggling Tottenham Hotspur take on first division Crystal Palace.
Everton also face a stern test from first division leaders Norwich City while Wolverhampton, bottom of the premier league, visit third division Kidderminster Harriers.
Two minor league sides, both from the Conference -- one promotion away from England's division three -- have reached the third round.
Accrington Stanley, the former league club who folded in 1962 and were reformed six years later, host Colchester United having beaten league sides Huddersfield and Bournemouth in previous rounds, while Telford visit first division Crewe Alexandra.