AC Milan and Barcelona can wrap up their Champions League group with two matches to spare and reduce their much-anticipated meeting next month to a mere friendly if both win their respective games on Tuesday.
Benfica, Real Madrid and Arsenal can also progress with wins in this week's matches while Chelsea will virtually ensure their presence in the last 16 if they take three points.
Bayern Munich's game at home to Napoli on Wednesday, following their 1-1 draw earlier this month, is the pick of the week's matches along with Real Madrid's visit to Olympique Lyon the same evening.
After a few early surprises, the group stage is again in danger of becoming a mere warm-up exercise for the big teams, contradicting the cliche which says there are no easy games in football.
Even Manchester United, who started out with two draws in Group C, could leave themselves with a relatively straightforward task to qualify if they beat Romanian champions Otelul Galati at home on Wednesday.
Apart from Benfica, the only surprise leaders in the eight groups are Cypriots APOEL Nicosia, who host Europa League champions Porto in Group G.
"We are happy to be top with five points. It's a big thing for APOEL and Cyprus. We are not top of the group through luck but we still know that everything can change with every match," coach Ivan Jovanovic said.
One point clear of Zenit St Petersburg and Porto, APOEL could drop to third place if they lose and the Russians beat Shakhtar Donetsk in the group's other game on Tuesday.
Bundesliga leaders Bayern dropped their first points of the campaign at Napoli but are still two points clear of the Champions League debutants at the top of Group A, where Manchester City, a further point behind, visit Villarreal who have yet to get off the mark.
That group is a stark contrast to Group H where AC Milan and Barcelona have taken seven points each from three games while BATE Borisov and Viktoria Plzen have one apiece.
Serie A champions Milan visit Belarusian champions BATE, where Barcelona have already recorded a 5-0 win, while Pep Guardiola's side visit Viktoria Plzen in Prague.
The Czech champions are unable to play at their own stadium as it does not meet competition standards.
Further wins for the big two will guarantee their places in the last 16 and reduce their meeting at San Siro on Nov. 23 to one of academic interest.
However, due to the mathematical intricacies of the Champions League, neither of the big two will qualify on Tuesday should one of them lose.
Group D leaders Real Madrid, the only team with maximum points from their three games, visit old rivals Olympique Lyon needing a win to render their final two games meaningless.
Real have yet to concede a goal and another win for them would also allow four-times European champions Ajax Amsterdam, who like Lyon have four points, to take a big step towards the last 16 by beating Croatian champions Dinamo Zagreb, so far without a point.
Benfica, twice European champions and five-times runners-up, will be certain of qualifying from Group C if they repeat this month's win over Swiss champions FC Basel at the Stadium of Light.
It would also help Manchester United, who have five points and could open up a four-point gap over Basel if, as expected, they beat rank outsiders Otelul Galati, who have yet to collect a point.
Arsenal, with seven points, are only one clear of Olympique Marseille in Group F but the combination of remaining fixtures means they will finish in the top two if they win on Tuesday.
In the same group, Bundesliga champions Borussia Dortmund, arguably the most disappointing side so far with one point, host Olympiakos.
Group E leaders Chelsea visit winless Genk, who they thrashed 5-0 two weeks ago, and another win will send them through if Valencia fail to beat Bayer Leverkusen at home.