Liverpool have a huge date in Paris while the two Manchester clubs attempt to qualify for the last 16 of the Champions League with a game to spare.
Tottenham seek to keep their qualification hopes alive at home to Inter Milan and know nothing other than victory will do.
Here, Press Association Sport runs the rule over an intriguing set of midweek fixtures.
Reds need to sort away-day blues
Liverpool have been exceptional in the Premier League this season but it has been a different story in Europe. Away defeats in Napoli and Red Star Belgrade have come as a shock and a similar story in Paris could leave last season's finalists in danger of crashing out at the group stage. Paris St Germain – beaten 3-2 at Anfield in September – need a win to keep their own qualification hopes alive and hope star men Neymar and Kylian Mbappe are fit after the pair missed the weekend win over Toulouse through injury.
Can Tottenham replicate their Premier League form?
Tottenham were effectively seconds away from Champions League elimination when Harry Kane claimed a last-gasp Wembey winner against PSV Eindhoven. Kane's goal offered a lifeline, although Spurs must probably beat Inter Milan on Wednesday and then Barcelona at the Camp Nou to make the last-16. Unrealistic? Possibly not if Spurs can shake off their lethargy in Europe and find the form which demolished Chelsea on Saturday and has brought seven wins in eight Premier League games.
Goals needed at Old Trafford
It was yet another day for Manchester United to forget on Saturday as Crystal Palace held them in a dour goalless draw. It was the fourth time in all competitions that United have drawn a blank at home, and Jose Mourinho's side have yet to score in the Champions League at Old Trafford. Group whipping boys Young Boys would appear to be the perfect opponents to end that run, especially as United won the reverse fixture 3-0 in September. Win, and United reach the last 16, providing Valencia do not win at Juventus. Anything else will simply increase the pressure on Mourinho.
Revenge on City agenda
It seems a long time ago that Manchester City were humbled at home by Lyon. The French side won 2-1 at the Etihad Stadium in the opening group game, but since then City have scored 11 goals in beating Hoffenheim and Shakhtar Donetsk twice. A last-16 place has yet to be secured, but that should be a formality given that Pep Guardiola's side have won 12 and drawn one (at Liverpool) since their Lyon slip. Avenging that September defeat will add extra motivation.