Following blistering starts to the Barclays Premier League season, both United and City will have to be taken very seriously in this edition of the Champions League.
However, two other perennial favourites are also in action on Wednesday, with Real Madrid travelling to Dinamo Zagreb, while Bayern Munich face a tricky trip to La Liga side Villarreal.
Here, ESPNSTAR.com takes an in-depth look at Wednesday's fixtures.
After splashing out during the summer to bring in Sergio Aguero and Samir Nasri to Eastlands, expectations will be high, and the pressure will be on for manager Roberto Mancini. However, the Italian may well be more concerned with his defence, rather than attack in their upcoming clash against Napoli, as the Serie A side boast goal-poacher Edinson Cavani in their ranks, who was the second-top scorer in Italy last season.
The fixture will also mark the first time these two clubs have clashed, as well as their debuts in the Champions League group stages.
The Citizens will be looking to make the best of this foray in Europe, given their last participation was in the 1968/69 season, where they were knocked out by Fenerbahce in the first round. Napoli, on the other hand, will look to extend their European record, as they have only lost only once in six European Cup games, against Real Madrid in Sept 1987.
However, their record against English clubs away has historically been dismal, having lost against Burnsley, Leeds and Liverpool in previous trips.
The fixture would have come at a very inconvenient time for Bayern, who already have Ivica Olic, Daniel Pranjic, and Breno in their treatment room. To make matters worse, Arjen Robben will also have to sit out as he is suffering from a groin injury, and has missed their last two Bundesliga fixtures. However, Villarreal will still be wary of Jupp Heynckes's side, as they demolished Freiburg 7-0 over the weekend ahead of this game.
The Yellow Submarines will still have room to feel confident though, being unbeaten in their last 11 home Champions League fixtures, and having won all seven of their Europa League ties at the Madrigal last season.
In the absence of Robben, Bayern will be looking for Mario Gomez to fire them up in Spain, and the striker will be looking to continue his scoring streak in the competition, having scored 12 goals in 14 Champions League starts.
Given this is the first competitive meeting between the two clubs, both sides will be looking to draw first blood in order to help them escape unscathed in this competitive group.
Inter Milan are clearly the kingpins of this group, given their relatively strong European pedigree compared to CSKA Moscow, Lille and Trabzonspor, and nothing but a smooth and hassle-free qualification for the next round is expected of new manager Gian Piero Gasperini, especially in light of their 4-3 defeat to Palermo last weekend.
However, constant upheavals at the Serie A side would not have helped their cause, given Gasperini is their fourth coach in less than a year. While Samuel Eto's exit to Anzhi in a big money move will certainly be mourned, given his experience at this level, Inter did reinforce well, after bringing in Diego Forlan and Mauro Zarate earlier this summer. The Nerazzuuri will also be pleased to have held off Manchester United's attentions for playmaker Wesley Sneijder.
Trabzonspor, on the other hand, will be pleased just to be in the competition at all, given they were initially elimiated but reinstated after Fenerbache were kicked out of the Champions League, thanks to a match-fixing scandal. However, given that they have never survived further than the first round of the competition, it could be a blood bath in the San Siro!
This clash could well influence which side snaps up the second spot in Group B to qualify alongside Inter Milan, and Lille will be keen to emulate the recent achievements of Lyon and Bordeaux in this competition by flying the French flag high and proud in Europe.
Given all that is at stake, this fixture is certainly crucial for Lille, especially given how the return fixture will certainly prove difficult for the Ligue 1 side, with Moscow's artificial playing surface proving a huge advantage for the Russian side.
This game will also mark the return of Joe Cole to the Champions League, as the Englishman has sought to revive his fading career by moving to Lille on loan from Liverpool, and all eyes will be on the midfielder.
Lille will be on a high ahead of this fixture, having beaten St Etienne 3-1 over the weekend, while CSKA Moscow will have to pick themselves up after a bruising 4-0 loss to Dinamo Moscow.
All of Europe would have been trembling after watching the manner that the Red Devils casually dismissed Arsenal 8-2 in the Barclays Premier League, and Benfica will certainly be wary of Sir Alex Ferguson's side, especially given they boast an 18-month unbeaten record away from Old Trafford in the competition.
The wily Scot has already started on his mind games ahead of the fixture, claiming that he is wary of Benfica's midfield, and could play a different side from the youthful one he has played in the Barclays Premier League so far.
Benfica's will be relieved that they reinforced their backline from last season, having brough in centreback Ezequiel Garay from Real Madrid, and custodian Artur from Braga. The Red Devils will be also watching out for Axel Witsel and Pablo Aimar in the centre of the park, as well as striker Oscar Cardozo and Nolito, who could trouble with their pace in counter-attacks.
This will certainly be an interesting fixture at St Jakob's Park, especially given how little is known about the Romanian side. Basel will be wary of Otelul Galati, who won their domestic title for the first time in their history last season.
The fixture would also mark a new record for Swiss sides in the Champions League, as Basel break new ground by making their fourth appearance in the competition. It will also mark the first competitive game between the two sides.
This fixture could well decide which club nabs second place to qualify alongside Real Madrid, and it will be exciting watching Dutch technique take on French flair at the Amsterdam Arena
Lyon will be marginal favourites, being semi-finalists in the competition last season, but will have to make do without striker Lisandro Lopez, who is still recovering from an ankle injury. They will also be wary of an Ajax in high spirits, with the Dutch side having won their last two Eredivisie fixtures, and sitting comfortably atop their domestic table.
Key to Ajax's hopes will be defenders Gregory van der Wiel and captain Jan Vertonghen, as well as midfielder Christian Eriksen and forwards Miralem Sulejmani and Kolbeinn Sigþórsson.
Eriksson, in particular, will be crucial to their hopes, and this could very well be his last season for the Dutch club, with several big names in Europe linked to a move for the cunning playmaker.
Lyon themselves are coming off a 2-1 victory over Dijon over the weekend, and are currently undefeated in France. They will rely on Michel Bastos and Bafetimbi Gomis in the absence of Lopez and chief playmaker Yoann Gourcuff. However, this Champions League campaign could also usher in yet another star for the Ligue 1 side, with Gueida Fofana keen to make his name in Europe. But manager Remi Garde will also have to conserve his resources for this fixture, given they have a huge crunch match against Olympique Marseille this coming weekend to worry about.
Coach Rémi Garde will want to get his team off to a good start in this competition but knows they have a key league match against rivals Olympique Marseille at the weekend, it will be interesting to see both what starting XI he chooses and how long the key players play in this match.
It's crunchtime for the Special One, as Real Madrid look to improve on their semi-final finish last season to return to winning ways in the Champions League. With a stable of stars like Cristiano Ronaldo, Mesut Ozil, Kaka, and Angel Di Maria in their ranks, there is no doubt that the La Liga giants are expected to progress in style.
Jose Mourinho will certainly not take Dinamo lightly though, and will warn his men about their Brazilian star Sammir, who helped the Croatian champions through six qualifying matches to make it thus far.
Dinamo will certainly be playing for pride at home, as they fly the flag for their domestic league, having won more Croatian League Championships than any clubs in their nation.