The Seagulls have lost just one of their last 12 games in all competitions and play the Mariners for the first time since 2014, when the pair met in League Two.
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Roberto De Zerbi's side are one of the most exciting teams in England and are looking to make it to the FA Cup semi-finals for just the third time.
Meanwhile, Grimsby have already knocked Southampton, Luton, Burton and Cambridge out to reach this point.
The Mariners are currently 15th in League Two and know this will be their toughest task yet.
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However, this competition is made for shocks, and a Grimsby win would be one of the biggest this season.
Brighton vs Grimsby: talkSPORT coverage
This FA Cup quarter-final clash will take place on Sunday, March 19.
Kick-off at the Amex is scheduled for 2:15pm.
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talkSPORT will have live commentary from the south coast, with Adrian Durham serving as your presenter.
Commentary will then come from Joe Shennan and former Chelsea defender Scott Minto.
talkSPORT.com will also have all the reaction from the match.
To tune in to talkSPORT or talkSPORT 2 through the website, click HERE for the live stream.
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You can also listen via the talkSPORT app, on DAB digital radio, through your smart speaker and on 1089 or 1053 AM.
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Brighton vs Grimsby: Team news
The hosts will be without Adam Lallana and Jakub Moder, while it will be too early for Tariq Lamptey as he battles to overcome a knee problem.
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And despite a place in a semi-final up for grabs, De Zerbi might decide to rotate his squad, with Robert Sanchez set to start in goal.
The visitors have no injury concerns but will be without George Lloyd, Mikey O'Neill and Stephen Wearne because they are cup-tied.
Two-goal hero against Southampton Gavan Holohan is expected to line up in the midfield as Paul Hurst's men look to become the first-ever fourth-division side to make it to an FA Cup semi-final.
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Brighton vs Grimsby: What has been said?
Brighton boss De Zerbi: "I believe in my players. They know it will be a difficult game.
"We can't think as if we are Premier League and they are fourth division or we will make a big mistake.
"Football changes but emotions stay the same. We are ready to try to arrive at Wembley.
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"We have to play with tempo against Grimsby and no arrogance - but if we play with our level against Leeds, Palace… we have a good chance of winning."
Brighton vs Grimsby: Match facts
Brighton and Grimsby Town haven't faced in any competition since February 2004 in a league match, won 2-1 by the Mariners with goals from Isaiah Rankin and Phil Jevons at Blundell Park.
This is the first time Brighton have faced Grimsby in the FA Cup since January 1930 in the third round, which was won by the Seagulls after a replay - at that time, they were in the Third Division South while the Mariners were a top-flight side.
Brighton are looking to reach an FA Cup semi-final for only a third time, also doing so in 1982-83 and 2018-19. This is only their fifth appearance in the quarter-final and only their second game at this stage against a team from a lower division, knocking out Millwall in 2018-19 on penalties after a 2-2 draw.
Grimsby Town this season are the first team in FA Cup history to eliminate five teams from a higher division in a single season in the competition (first round onwards). This is their first FA Cup quarter-final since 1938-39, when they beat Chelsea 1-0 as a top-flight side, and will be the biggest gap between quarter-final appearances (84 years), breaking Reading's 83-year record (1927-2010).
As a top-flight side, Brighton have progressed from 14 of their 16 FA Cup ties against sides from a lower division, failing only against third tier Oxford United in 1981-82 and Championship side Sheffield Wednesday in 2019-20. Their two such ties against League Two teams have seen them progress, against Coventry in 2017-18 and Newport County in 2020-21.
Since the fourth tier of English league football was created in 1958-59, Grimsby are only the fifth side from that division to feature in an FA Cup quarter-final. All four previous sides have been eliminated: Oxford United in 1964, Colchester United in 1971, Bradford City in 1976 and Cambridge United in 1990.
This will be the first FA Cup quarter-final to see a Premier League side play at home against a team from outside the top-flight since 2016-17, when two such games were played and won by the home sides - Arsenal 5-0 Lincoln City and Tottenham Hotspur 6-0 Millwall.
From the first round onwards in this season's FA Cup, no team has netted more goals than Grimsby Town (15, level with Wrexham). It's the most by a fourth tier side in a season since Crewe in 1992-93 (also 15), with Colchester the last fourth tier team to net more than 15 (18 in 1970-71). All 15 of their goals have been against teams from a higher division, with only Tottenham in 1900-01 - then a non-league team - scoring more (16) against sides from a higher division in a season from the first round onwards.
Brighton manager Roberto De Zerbi hasn't managed against a team from the fourth tier of a league system since the 2013-14 campaign, when he managed in Italian Serie D with Darfo Boario. His only previous cup quarter-final was in 2015-16 with Foggia in the Coppa Italia Lega Pro, drawing 1-1 with Akragas before progressing on penalties and going on to win the competition that year.
Brighton's Kaoru Mitoma has been involved in a goal in each of his three FA Cup appearances this season, scoring once and assisting twice for the Seagulls. Among Premier League players in the FA Cup this season, only Fulham's Manor Solomon has completed more take-ons (14) than Mitoma (8) and only Liverpool's Mohamed Salah (23) has had more touches in the opposition than he has (19).