Manchester City's home clash with Pep Guardiola's reigning European champions Bayern Munich will capture the imagination of most on Wednesday evening, while the pressure is on David Moyes as Manchester United face Shakhtar Donetsk.
AFP Sport looks ahead to all eight of Wednesday's fixtures on matchday two:
Bayer Leverkusen (GER) v Real Sociedad (ESP)
Both Leverkusen and Real Sociedad are looking to get their campaigns up and running after suffering defeats on matchday one. Leverkusen went down 4-2 to Manchester United at Old Trafford in their opening game, while the Basque side lost 2-0 at home against Shakhtar Donetsk.
Sami Hyypia's team will fancy their chances of registering all three points at the BayArena, however, fresh as they are from a third straight Bundesliga win on Saturday against Hannover. While they are enjoying their best start to a league season, Real, in contrast, have gone six games without a win, their worst sequence of results in two years, and coach Jagoba Arrasate is without Esteban Granero and the influential Xabi Prieto for the trip to Germany.
Shakhtar Donetsk (UKR) v Manchester United (ENG)
A trip to deepest Ukraine is surely the last thing that David Moyes wanted as the pressure builds on the Scotsman following Manchester United's worst start to a domestic campaign in 24 years. United's 2-1 home loss to West Bromwich Albion on Saturday was their third defeat already in just six Premier League games, but at least Moyes oversaw a 4-2 win against Bayer Leverkusen in his opening Champions League group game in charge a fortnight ago.
Wayne Rooney scored twice in that game and Moyes - who has admitted his side lack sufficient world-class talent to win the Champions League - will need the England star at his best in the Donbass Arena.
Shakhtar needed a late comeback to draw 2-2 away to unheralded local rivals Metalurg at the weekend but their European opener was an impressive 2-0 win at Real Sociedad and they have previous against English opposition, beating Chelsea at home last season.
Real Madrid (ESP) v FC Copenhagen (DEN)
After the humiliation of losing the Madrid derby at the weekend, Real coach Carlo Ancelotti knows the importance of getting back to winning ways in Europe.
The visit of a Copenhagen side who sit second from bottom of the Danish league and lost 3-2 to Brondby at the weekend should provide the perfect opportunity for the Spanish giants, although Stale Solbakken's men did hold Juventus in their opening Group B game.
Iker Casillas will make his first appearance at the Santiago Bernabeu in almost nine months as Ancelotti again gives the nod to the Spain captain ahead of Diego Lopez in goal in Europe. Gareth Bale could also make his first start at home for his new club, who thumped Galatasaray 6-1 away last time out.
Juventus (ITA) v Galatasaray (TUR)
After being held by Copenhagen two weeks ago, Italian champions Juventus chase a first win in Group B as they play host to Galatasaray, who are seeking an improvement on their 6-1 thumping at the hands of Real Madrid.
Antonio Conte's Juve, who won the last of their two European Cups in 1996, beat city rivals Torino 1-0 at the weekend thanks to a Paul Pogba strike and remain unbeaten in all competitions this season, even if they trail Roma by two points at the top of Serie A.
The Turks come into the game with a new coach who is familiar with taking on Juve. Former Lazio, Inter Milan and Manchester City boss Roberto Mancini was on Monday appointed as the replacement for the sacked Fatih Terim. His remit is to revive a side who sit in mid-table in their domestic league with just one win from five games.
Anderlecht (BEL) v Olympiakos (GRE)
Belgian champions Anderlecht and Greek title-holders Olympiakos are, on paper, the outsiders to qualify from Group C and both were beaten on matchday one. Anderlecht went down 2-0 away to Benfica while Olympiakos were outclassed in a 4-1 home loss to Paris Saint-Germain.
The Belgians have a proud history and beat AEK Athens home and away when they last faced Greek opponents in the Europa League two years ago, but John Van den Brom's men are fourth in their domestic Pro League, nine points behind leaders Standard, and appear ill-equipped to make an impact in this competition. Olympiakos, who have lost 99 times in Europe, are top of the Greek Super League without defeat and may fancy their chances of recording an away win here.
Paris Saint-Germain (FRA) v Benfica (POR)
Paris Saint-Germain underlined their status as Group C favourites by thumping Olympiakos in Greece two weeks ago, and can take a big step towards qualifying for the last 16 by beating Benfica at the Parc des Princes.
Laurent Blanc's side have struggled to convince so far this season, but remain unbeaten in all competitions while Benfica - who beat Anderlecht 2-0 in their opening game - are only fifth in the Portuguese top flight, five points behind leaders Porto.
However, the Lisbon club can expect a warm backing in the French capital, which is home to a large Portuguese population. PSG will be without captain Thiago Silva due to injury as they chase revenge for a defeat to the same team in the Europa League last 16 in 2011.
CSKA Moscow (RUS) v Viktoria Pilsen (CZE)
The poor state of the Arena Khimki pitch in Moscow led to this match being moved 700 kilometres to St Petersburg. CSKA and the Czech champions both lost their opening games and are expected to fight it out for third place in Group D behind Bayern Munich and Manchester City.
CSKA's preparations for this encounter have not been the best - they lost 2-0 at Terek Grozny at the weekend and have failed to win, or even score, in their last three domestic matches. In contrast, Pavel Vrba's Pilsen are still unbeaten in the Czech league and have won five and lost two of their last seven European away games.
Manchester City (ENG) v Bayern Munich (GER)
This encounter at the Etihad Stadium promises to be fascinating, with City manager Manuel Pellegrini coming up against Bayern's Pep Guardiola again. The pair are familiar with one another from their time in Spain, in particular when they occupied the dugouts at Real Madrid and Barcelona respectively in 2009-10.
The two Group D favourites meet on the back of wins in their opening matches, with City triumphing away to Viktoria Pilsen while Bayern beat CSKA Moscow at home.
Goals from David Silva and Yaya Toure gave City a 2-0 win when they played host to Bayern in this competition two years ago, but the English side have failed to progress beyond the group stage in either of the last two years while Bayern are the reigning European champions.