Atletico Madrid are hoping to recover from losing to Liverpool on matchday three with a repeat of their Anfield heroics last March.
Paris Saint-Germain and Manchester City will look to take bigger steps towards the last 16, while Real Madrid will go in search of another big win against Shakhtar Donetsk.
Inter can put themselves in a good position to progress, too, although city rivals Milan have got much more of a fight on their hands.
Here are some of the key Opta facts for Wednesday's Champions League matches...
Liverpool v Atletico Madrid: Can Suarez improve rotten recent record?
Atletico were winners at Anfield on their last visit as they claimed a 3-2 victory in the last-16 second leg in March 2020. Indeed, Liverpool have only twice beaten Spanish teams at home in 13 attempts in the European Cup and Champions League.
That said, the Marcos Llorente-inspired game last year was one of only two out of 22 at home that Jurgen Klopp has lost in this competition as Reds manager, while Diego Simeone is chasing what would only be the second instance of a third successive away win in the tournament with Atleti.
Luis Suarez will hope to haunt his old side, although recent history is against him: he's only scored one for Atleti in nine Champions League games, and none from open play. Mohamed Salah, meanwhile, needs one more goal to equal Steven Gerrard as Liverpool's top scorer in the competition at Anfield (14).
Manchester City v Club Brugge: Bad omens for Belgian champions
City's 5-1 triumph in Bruges on matchday three took their tally to six wins in seven European games against Belgian opposition, while Brugge are now without a victory over English teams in 13 attempts dating back to February 1995.
Since Pep Guardiola took charge, City have won 80 per cent (20 out of 25) of home Champions League matches, which is the best record for a coach at a single club in the competition among those to take charge of 20 or more. A first win on English soil for Brugge looks unlikely.
Might this be a chance for Raheem Sterling to impress? The England forward has been directly involved in 24 goals in 27 home Champions League games for City, a tally surpassed only by Sergio Aguero (27).
RB Leipzig v Paris Saint-Germain: Nkunku could outshine Messi
PSG have only lost one of their past nine away games in the group stage, but that defeat was against RB Leipzig last season. It was the only time in the previous seven meetings with French sides that Leipzig emerged victorious.
He might be enduring a difficult time in Ligue 1, but Lionel Messi has managed three goals in three games in Europe for PSG. His double in the reverse fixture was his 34th in the competition, something only Cristiano Ronaldo (37) can better.
However, perhaps the most in-form player in 2021-22 is Leipzig's Christopher Nkunku, who has been involved in the most open-play sequences ending in a goal (six) among Champions League midfielders this season. And he has four goals of his own from the first three matches.
Real Madrid v Shakhtar Donetsk: Another big win on the cards with Benzema
Madrid's 5-0 win over Shakhtar on matchday three means the past five meetings between these teams have seen an average of 4.6 goals scored per game. In fact, Los Blancos have scored 15 times in five Champions League matches against Shakhtar: that average of three per game is their best figure against a side they have faced on at least five occasions, apart from Galatasaray (3.4 per game).
Shakhtar are one of just three sides yet to score in this season's group stage, but with Madrid having lost three of their previous eight home games in the competition, this could be a good opportunity.
They will need to stop Karim Benzema and Vinicius Junior, though: they are the two players with the most involvements in shot-ending sequences in 2021-22 (31 and 34, respectively). Plus, Benzema is on a run of 10 goals in 10 home games in the competition.
Sheriff v Inter: Nothing shot-shy about Inzaghi's men
Inter ended Sheriff's 11-game unbeaten run in Europe last time out and will now look to secure consecutive Champions League victories for the first time since October 2018.
The Nerazzurri have lost just once in their previous five Champions League away matches, but Sheriff are unbeaten in their most recent five European games on home soil, excluding qualifiers. They've also won the past two.
Inter certainly have the variety to break down Sheriff's stubborn defence. Each of their previous 17 away goals in the competition have come from open play, while their 29 shots in the meeting on matchday three were the most by an Italian side in a Champions League game since at least 2003-04.
Borussia Dortmund v Ajax
45 – Ajax's 4-0 win over Dortmund last time out was the biggest victory by a Dutch side over a German team in Europe since November 1976, when Feyenoord defeated Kaiserslautern 5-0 in the UEFA Cup.
8 – Sebastien Haller has been directly involved in more Champions League goals this season than any other player (eight – six goals, two assists). Among debutants in the competition since 2003-04, this is the highest such figure over a player's first four appearances and one more than Erling Haaland managed.
Milan v Porto
3 – Milan are one of just four sides this season to have lost all three group games. They are on a five-game losing run in the competition, the worst such streak in their history.
1 – Since scoring four for Chelsea against Sevilla in December 2020, Olivier Giroud has scored only once in 250 minutes of play in the Champions League.
Sporting CP v Besiktas
5 – Paulinho has been directly involved in three of Sporting's five goals (two scored, one assisted) in this season's Champions League. Their last player to manage more goals and assists combined in a single season was Nani in 2014-15 (six).
10 – Michy Batshuayi has attempted 10 shots for Besiktas in the Champions League in 2021-22 without scoring. Over the first three matchdays, only Inter's Lautaro Martinez (12) had more shots without finding the net.