For Chelsea, who have already failed to win four trophies this season and are 14 points adrift in the title race, the trip to Southampton could be problematic.
FA Cup third round is a weekend the top clubs fear
Few competitions generate cliches like the FA Cup. Given a history dating to 1871 and a tradition of underdogs impressing against favourites, expect to hear a lot about "the magic of the FA Cup" over the next 48 hours.
But what about the opposite? For those burdened with expectation, this can be a no-win situation. Come tomorrow night, several may be suffering from the misery of the FA Cup.
For Arsenal, in their eighth season without silverware, tomorrow's tie at Swansea takes on crucial proportions.
For Chelsea, who have already failed to win four trophies this season and are 14 points adrift in the title race, the trip to Southampton could be problematic. United's visit to West Ham may not have the same consequences but it promises to be awkward nonetheless.
Should Liverpool and Everton lose at Mansfield or Cheltenham respectively, non-league and League Two teams, they would be filed in the category of disastrous defeats.
Newcastle United and Sunderland, who have not won major silverware since 1969 and 1973, face demanding games at two of the Championship's more gifted teams, Brighton & Hove Albion and Bolton Wanderers. Relegation-threatened Reading and Wigan Athletic take on League One's upwardly-mobile teams, Crawley and Bournemouth.
For the Premier League sides, this can be the most chastening weekend of the season. Cliche has it that the FA Cup is romantic. But only for the outsiders.
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