Manchester City will enter the last-chance saloon on Wednesday, while Arsenal are looking to get their European campaign back on track.
Elsewhere, Paris St Germain and AC Milan will be looking to secure their safe passage to the knockout stage with one game to spare.
Arguably the most intriguing tussle of the night will take place at the Etihad Stadium, where Manchester City have no margin for error in a home date with Real Madrid - which can be seen live on Sky Sports 2HD and in Sky 3D.
The Blues simply must win to keep their faint hopes of reaching the last 16 alive, with group stage elimination for a second successive season staring the Premier League champions squarely in the face.
Jose Mourinho would like nothing more than to be the man to end City's challenge, with the Real boss back on English soil and in determined mood.
A point could be enough to see Los Blancos safely through, depending on the result in Group D's other fixture.
Table-topping Borussia Dortmund require only a draw on the road at Ajax to progress, while the hosts must take something from the game - preferably a win - and hope City do the business against Real to keep them in the hunt.
Arsenal returned to winning ways in some style over the weekend, in a derby demolition of arch-rivals Tottenham, and will be looking to carry that momentum into a continental clash with Montpellier - in a game which will be screened live on Sky Sports 4HD.
Taking only a point from back-to-back fixtures with Schalke has seen the Gunners slip from the summit in Group B and leave them with work to do to ensure their sage progress to the next stage.
Their fate does, however, rest in their own hands and qualification will be wrapped up on Wednesday with a victory at Emirates Stadium.
Montpellier, though, still have plenty to play for, with maximum points required from their final two fixtures if they are to pick up the consolation prize of a place in the Europa League.
Elsewhere in the group, Schalke will go through with victory over notoriously poor travellers Olympiakos, while the Greek outfit know success in Germany would put them in pole position to claim a top-two finish.
Paris St Germain have struggled domestically of late, but they are determined to make a noise in Europe and can offer their Qatari owners a return on their sizeable investment with victory over Dynamo Kiev - with three points all they require to make the last 16.
Porto are already assured of a place in the knockout stage but will guarantee themselves top spot in Group A if they see off whipping boys Dinamo Zagreb and PSG drop points in the Ukraine.
AC Milan have conquered Europe on seven previous occasions and despite their troubles in Serie A, they can move a step closer to another continental crown in midweek with victory over Anderlecht.
A win for the Rossoneri would see them join Malaga in the last 16, with the Spaniards looking to overcome Zenit in Wednesday's early kick-off and wrap up top spot in Group C.