Lionel Messi is in line to make his 150th Champions League appearance and his first with Paris Saint-Germain on Wednesday.
Mauricio Pochettino's men travel to Club Brugge and Messi is about to partake in his first European campaign without Barcelona, while Manchester City host RB Leipzig.
Liverpool and Milan renew rivalries in the competition for just the second time since the 2004-05 final between the pair but the Serie A side have a woeful record against English teams.
Inter have a similarly poor record against Spanish teams and they face Real Madrid, with Karim Benzema edging towards another goalscoring landmark.
Here, Stats Perform takes a look at the key Opta data ahead of Wednesday's fixtures.
Inter v Real Madrid: Benzema looks to edge past former Galactico Raul
Inter have lost four of their last five against Real Madrid but Los Blancos have only won one of their previous eight away games against Wednesday's opponents as they prepare for a replay of last year's group stage outing.
However, Inter have not won against a Spanish team in Europe's premier competition since 2010 and Madrid have been victorious in 12 of their last 13 against Serie A outfits.
Carlo Ancelotti has Karim Benzema among his ranks and the forward will appear in his 17th consecutive campaign as he looks for his 72nd goal to move ahead of Raul (71) into fourth in the all-time scoring list.
Manchester City v RB Leipzig: Guardiola's group stage dominance
Manchester City are unbeaten in their last 17 group-stage ties and, since Pep Guardiola was appointed, they have lost just three of 30 at this stage of the competition.
The hosts are eyeing their 50th win in their 91st game as they look to become the second fastest to the half-century, while RB Leipzig have lost three of their last four against English opposition.
City's attacking riches could thrive at Etihad Stadium, too, Ferran Torres has scored four in his last six appearances in Europe - a goal every 90 minutes - and Riyad Mahrez has been involved in 22 goals in 28 starts for Leicester City and his current side in the Champions League.
Liverpool v Milan: Istanbul replay ends Rossoneri's seven-year wait
Milan will appear in their first Champions League since 2014, their first fixture a replay of the memorable 2004-05 final that saw Liverpool triumph.
Stefano Pioli's men have won just one of their last 13 against English opponents in European competition, while the Reds have lost just one of their last 12 group-stage games at Anfield in Europe under Jurgen Klopp.
Mohamed Salah (25) is one of two Liverpool players – along with Steven Gerrard (21) – to score 20+ times in the competition but Sadio Mane (19) could join them with a goal on Wednesday to become the fourth African to the 20-goal mark.
Club Brugge v Paris Saint-Germain: Pochettino's attacking riches
Paris Saint-Germain have netted 21 goals across six games against Belgian opposition – winning five and drawing once – while Club Brugge have only won one of their six opening games.
Lionel Messi – the second all-time leading scorer in the competition – could make his first PSG continental appearance, having scored 120 goals and provided 35 assists in 149 games for Barcelona against teams from 17 nations.
The visitors also boast half of the six players to be involved in 30+ goals in the competition in the last four seasons, with Kylian Mbappe (37), Messi (36) and Neymar (31) all doing so.
Atletico Madrid v Porto:
41 – Diego Simeone has won 41 of the 79 Champions League fixtures he has managed since 2013-14, with only Pep Guardiola (56) picking up more wins in this period.
4 – Porto have won four of their last five away games in the competition, their only loss coming against eventual runners-up Manchester City last term.
Besiktas v Borussia Dortmund:
1 – Besiktas have only collected one win in their last 10 home games in the Champions League and two of four defeats in that run have come against Bundesliga sides.
100 – Borussia Dortmund have a 100 per cent record against Turkish opposition in the Champions League, though all four wins have come against Galatasaray.
Sheriff Tiraspol v Shakhtar Donetsk:
1 – Sheriff Tiraspol are the first ever Moldovan team to feature in the Champions League proper. They are unbeaten in their last nine in European competition.
3 – Shakhtar Donetsk have only been beaten three times in their last 11 games as they went unbeaten against Real Madrid and Inter in the group stages last season.
Sporting CP v Ajax:
36 – Aged just 36, Ruben Amorim becomes the second youngest Portuguese manager in the competition's history, after former Chelsea manager Andre Villas-Boas (33) in 2011.
2 – Ajax have only lost two of 10 games against Portuguese opponents since the inaugural European Cup. However, just two of these games have taken place this century.