It will be an emotional night for Madrid's Cristiano Ronaldo as he faces his former club for the first time, but there are a number of key battles that will play an important role in deciding which side progress to the last eight.
With that in mind, Sports Mole has picked out five crucial clashes that could ultimately decide the outcome of European tie.
Cristiano Ronaldo vs. Rafael
Ronaldo warmed up for the match with yet another hat-trick in Madrid's 4-1 win over Sevilla at the weekend. However, he will come up against arguably the best right-back in the Premier League when Manchester United come to town. While twin brother Fabio's career has stuttered, Rafael has grabbed the full-back position at the English club.
His tenacity and energy will be key in the battle against Ronaldo, who will have to deal with the emotion against the first club he ever loved. Ronaldo will roam across the pitch throughout the evening, purely because he plays where he wants to, but Rafael will be given the task of shackling the Portuguese. It will be a test of just how far the young Brazilian defender has come this season.
Mesut Ozil vs. Phil Jones
Although Phil Jones's inclusion has yet to be confirmed, it is likely that the England international will shake off an injury to start in the Spanish capital. He was blighted by injuries in the early part of the season, but his performance against Everton on Sunday, where he man-marked Marouane Fellaini, was arguably his best display in a United shirt. However, on Wednesday he will come up against one of the best playmakers in world football.
Ozil has not quite hit the goalscoring trail that was expected this season, but his ability to craft and probe will be key to Madrid's chances of progressing to the quarter-finals. It is understood that he will start as the most advanced of a three-man midfield that also includes Xabi Alonso and Sami Khedira, with Jones's evening consisting of marshalling the German.
Xabi Alonso vs. Michael Carrick
It would be fair to say that Carrick's United career is enjoying somewhat of a second wind this season. The 31-year-old had come in for a large amount of criticism from pundits and supporters alike over the previous 12 months or so for what was perceived as sideways passing that never caused a threat to the opposition. Fast-forward to the present day, though, and his displays in a red shirt this campaign have been hailed. The arrival of Robin van Persie has something to do with that, having given the England international another target to find.
Alonso is to Madrid what Carrick is to United. Arguably, the former Liverpool midfielder actually possesses a greater passing range than his United compatriot. These two will be charged with the task of retaining possession for their side. Whoever does it better will give their team the best chance of picking up a positive result.
Sergio Ramos vs. Robin van Persie
It looks as though in terms of the Premier League title race, Van Persie has made the difference for United this season. He's the club's leading goalscorer and has found the net against the likes of Manchester City, Chelsea and Liverpool. Tomorrow provides him with the chance to make his mark for the club in European competition. His record for Arsenal makes for positive reading, having scored 20 times in 52 Champions League appearances.
The man charged with the task of keeping the Dutchman quiet will be Ramos. His importance to Madrid has been seen recently when he was forced to sit out four La Liga matches through suspension. If he can do what so many English clubs have failed to do this season and shackle Van Persie, he will have nullified United's major goalscoring threat.
Sami Khedira vs. Wayne Rooney
Aside from Ronaldo, Khedira has arguably been Madrid's best player this season. Signed as a defensive midfielder, he has found himself in more attacking positions in this campaign, making his mark as one of the finest in his position. His attacking exploits will be curbed on Wednesday, however, as he is given the task of shackling an in-form Rooney.
The English striker is expected to play behind Van Persie in an attempt to provide a link between the midfield and the Dutch forward. In the spells where United do not have the ball, Rooney could also drop deeper and go head-to-head with Khedira in the same position. With Rooney central to United's chances in this tie, it could be argued that this is the key battle.