The competition is famous for producing upsets, and it was Sheffield United and Grimsby Town's turn to do just that this time round.
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Premier League Southampton hosted the League Two outfit, the lowest ranked side left in the FA Cup.
Gavan Holohan scored scored two penalties on the south coast to give his side a shock lead.
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The Saints replied through Duje Caleta-Car, but they were eventually handed an embarrassing 2-1 defeat on their home turf.
Tottenham are searching for their first trophy since 2008, and their wait for silverware is set to continue.
Sheffield United reached their third FA Cup quarter-final in four years courtesy of a 1-0 win, with Iliman Ndiaye scoring the winner late on.
Manchester United, fresh from their Carabao Cup triumph last weekend, safely made it through to the quarter-finals, although West Ham made them sweat for their 3-1 win at Old Trafford.
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After the visitors took the lead through Said Benrahma, a Nayef Aguerd own goal and late finishes from Alejandro Garnacho and Fred saw Erik ten Hag's side retain their hopes of winning a four trophies this season with Man United also in the Europa League and Premier League title race.
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Championship leaders Burnley also progressed the last eight as Connor Roberts netted in the 90th minute against ten man Fleetwood.
In the quarter-finals, Burnley boss Vincent Kompany will to his old club Manchester City as United host Fulham.
Grimsby will return to the south coast, this time to Brighton, and Sheffield United welcome the visit of Blackburn.