Arsenal are wary of suffering more misery when they take on Sunderland in the FA Cup, while Crawley Town and Stevenage will be dreaming of giant-killings against Stoke City and Tottenham Hotspur.
The fifth round also contains outings for Premier League clubs Liverpool, Chelsea, Everton, Norwich City and Bolton Wanderers.
Arsenal were on Wednesday humiliated in their UEFA Champions League last 16 first leg against AC Milan as they were hammered 4-0 at the San Siro in what was one of the English club's worst performances for several years.
The fallout from the horror show saw manager Arsene Wenger on Thursday reportedly go 'crazy' at his squad during training and players could well be fighting for their futures for the rest of the season.
A trip to Sunderland on Saturday evening is therefore far from ideal for Arsenal following Martin O'Neill's much-publicised rejuvenation at the Stadium of Light.
But Wenger's men have inflicted one of the three defeats O'Neill has suffered as Sunderland boss after Thierry Henry's late goal grabbed a 2-1 win on Wearside last weekend.
The Gunners, though, have won only two of their last seven FA Cup ties away from home.
The romance of the FA Cup will on Sunday be fully evident in Stoke's trip to League Two Crawley.
In the space of four days, Tony Pulis' side will have gone from rubbing shoulders with the European elite and Spanish heavyweights of Valencia to a tricky domestic cup tie at Broadfield Stadium.
Crawley are the lowest ranked club left in this season's FA Cup and boss Steve Evans will be aspiring towards a piece of history against last season's defeated finalists.
Stoke, though, have won their last four FA Cup matches away from home, keeping a clean sheet in three of those games, and Pulis will not expect any complacency.
League One Stevenage could on Sunday also cause an upset when they welcome Tottenham to Broadhall Way.
England manager-elect Harry Redknapp will know he is now, more than ever, headline material whether he wins, loses or draws after what has been a dramatic 2012 to date.
Amid Tottenham's Premier League title challenge, the club's manager has been cleared of tax evasion and has also been installed as runaway favourite for the England job.
Stevenage, who have yet to concede an FA Cup goal this season, will aim to halt the Redknapp juggernaut, but Tottenham have not lost in the FA Cup to a lower division side since Leicester in 2006.
With a challenge for the top four in the Premier League looking far from certain, Carling Cup finalists Liverpool want a cup double and will be confident ahead of Sunday's tie against Brighton & Hove Albion at Anfield.
Striker Luis Suarez will be under scrutiny given his behaviour in last weekend's defeat by Manchester United and subsequent apology, and his club will be expecting a less controversial outing.
Brighton's Uruguayan manager, Gus Poyet, has defended his compatriot throughout the racism row with Patrice Evra, but any sentiment will be put on hold when revenge is in the air.
Liverpool in September knocked Poyet's Championship play-off hopefuls out of the Carling Cup and he will be determined to set the record straight in the first FA Cup meeting between the two clubs in 21 years.
Chelsea manager Andre Villas-Boas is under increasing pressure at Stamford Bridge and will know on Saturday lunchtime anything less than victory over Birmingham City could push his head further toward the block.
The Londoners have not won in four Premier League games, including last weekend's shock defeat at Everton, and are involved in the battle for the top four.
An awkward game against Birmingham could cause more problems, as Chris Hughton's side have not lost in 10 games to leave them sitting fifth in the Championship.
Chelsea, though, have won 13 and lost just one of the last 19 matches in all competitions with their former Premier League rivals.
Fresh from their win over Chelsea, in-form Everton, who have also defeated Manchester City in one of their last three Premier League games, host Blackpool hoping to avoid another home disappointment in the FA Cup.
David Moyes' side have been eliminated in four of the last five FA Cup seasons at Goodison Park and two of their last three exits at home have come at the hands of lower league teams.
It would appear Saturday's game will be the place to be for goals after the last meeting between these two sides was Everton's 5-3 win in last season's Premier League.
Indeed, in the last two meetings between the pair there have been 12 goals, with a 2-2 draw at Bloomfield Road preceding the thriller at Goodison Park.
Blackpool boss Ian Holloway had spoken of his disappointment at failing to beat Everton in the Premier League before ultimately suffering relegation and will have eyes on addressing that record.
Norwich's dream season sees them sitting eighth in the top flight and Saturday's fixture against Leicester City at Carrow Road will be a reminder of their success contrasted with the visitors' fall from grace.
Former Premier League outfit Leicester have experienced a troubled campaign and, having earlier in the season parted company with Sven Goran Eriksson, they only sit mid-table in the Championship under Nigel Pearson.
A row has emerged regarding Leicester's ticket allocation at Carrow Road to add a bit of extra spice to the tie, but Paul Lambert will take confidence from winning both league meetings - in which there were 12 goals across two matches - against the Foxes last season by a one-goal margin.
Owen Coyle's Bolton have suffered a season to forget and are in serious danger of Premier League relegation, which would likely have dire consequences at the Reebok Stadium.
A defeat on Saturday to Championship strugglers Millwall, who have won just two of their last 12 league games, at The Den would cast a further shadow over the campaign.
Millwall have needed replays in both rounds previous to the fifth and they have never beaten Bolton in the FA Cup in two attempts.
What will be the outcome in the match Sunderland vs Arsenal?