Tuesday could be the day in which the lights go out on Manchester City's UEFA Champions League adventure, while Arsenal need to reignite their challenge.
Elsewhere, in the reverse fixtures from Matchday Three, there is every chance that a number of sides will be celebrating their safe passage to the knockout stages with two games to spare.
Manchester City must beat Ajax at the Etihad Stadium in midweek to stand any chance of keeping their Champions League dream alive, and even that may only delay a second morale-sapping slump out of Europe's premier club competition in as many seasons.
Roberto Mancini and his side have not come to terms with life at the continent's top table, with one of the toughest groups around posing them questions they have had no answer to.
Ajax stuck the knife into the Blues a little deeper last time out, running out 3-1 victors in Amsterdam, and the Dutch champions will take plenty of heart from the fact that they beat Manchester United at Old Trafford in the Europa League last season.
With City's hopes hanging by a thread, they will be looking for others to do them a few favours - with Mancini likely to be keeping his fingers crossed for a Borussia Dortmund victory when they travel to Real Madrid in Group D's other fixture.
Arsenal are far from guaranteed to be playing Champions League football in the New Year, with a lacklustre performance against Schalke in their last outing offering them a rude awakening.
The Gunners will need to raise their game considerably for the return date, live on Sky Sports 2 HD, especially as the German outfit will have home soil advantage on Tuesday night.
English sides have fared admirably in Gelsenkirchen in recent times - with Manchester United and City leaving with victories - but Schalke know success in their latest encounter could, if other results go their way, see them through and able to focus on a Bundesliga title charge.
For Schalke to progress, they must beat Arsenal and see Olympiakos slip up at home to out-of-sorts French champions Montpellier - but that contest has plenty riding on it as it could end up being a decider as to who finishes third in Group B and drops into the Europa League.
Porto's task on Tuesday is much more straightforward, with the Portuguese outfit heading into a meeting with Dynamo Kiev knowing that a fourth straight success will see them into the knockout stage.
Paris St Germain can all but wrap up the second qualifying spot in Group A with victory at home to Dinamo Zagreb, a side that remain pointless and stuck in the midst of a nine-match losing sequence in Champions League competition.
Only four sides boast 100 per cent records on Matchday Four and Malaga will be looking to preserve theirs, and keep a fourth clean sheet, when they travel to San Siro to take on an AC Milan side that bagged five goals in front of their own supporters at the weekend.
Any slip-up from Milan will open the door to Zenit St Petersburg in the race for a top-two finish in Group C, with the Russian outfit out on the road on Tuesday looking to pile further misery on an Anderlecht side that are yet to open their scoring account in this season's Champions League.