The two teams picked up a 1-1 draw in their opening leg meaning that this one is evenly poised for either side, who have both been in tremendous form of late.
Real Madrid have picked up back-to-back wins over Barcelona in the space of a week—the latter coming without Cristiano Ronaldo for an hour of play—while Manchester United have continued to build on their lead atop the English Premier League.
The Red Devils haven't lost since November in 2012 and have won 14 of their last 16 matches—defeating Manchester City, Liverpool and Everton in that time. Moreover, they've allowed just three goals against in their past nine matches—making this one a truly fascinating encounter indeed.
What should we be looking out for heading into this key Champions League clash? Here's the biggest questions to keep an eye on in this must-watch fixture.
How Will Cristiano Ronaldo Fare Back at Old Trafford?
The talk of this one certainly starts with superstar winger Cristiano Ronaldo, who will be returning to Old Trafford for the first time since his transfer.
The Portugese international has been in electric form of late and has been simply unstoppable right throughout the Champions League so far, with even the man-marking presence of Phil Jones in the first leg unable to keep the 28-year-old from finding the back of the net.
His presence in this second leg will be crucial for Madrid, for if he can thrive and get their attack going once more, United will find it tough to get going. The Red Devils will likely find themselves bogged down in midfield and defense—something that they were perhaps lucky to survive in the first leg.
If that happens again in the second leg, it will be tough for them to progress, so look for a high backline to try and press Ronaldo early. United's ability to shut him down (or inability as it might be) could well be the defining mark of this fixture.
Can Wayne Rooney Be Stopped in Attack?
Alternatively, at the other end of the field, Manchester United's attacking direction and chances will center around the ability of Wayne Rooney in the middle.
Rooney has proven to be a dynamic finisher in front of goal who has a great ability to build the play from behind the attacking line. He showed that to be the case against Norwich City recently, with a near perfect two-assist performance accompanied by a goal for good measure.
If he can repeat that again here and get the likes of Robin van Persie and Shinji Kagawa going, the Red Devils will certainly like their chances of success.
The key for Los Blancos will be cutting out the space in front of the defensive line for Rooney to run at and assess his options. Madrid could shift someone like Raphael Varane onto Rooney rather than using the Frenchman on Van Persie to try and shut Rooney out completely, but it seems more likely that Xabi Alonso will be utilized as a defensive midfielder on the England international.
Much like Ronaldo, how Rooney fares in this match—successfully or unsuccessfully—will have a profound impact on the result.
What Will Jose Mourinho Conjure Up?
The reason this question is so big is the changes that Mourinho was prepared to make against Barcelona in their recent La Liga El Classico match. The wily manager rested several big stars in order to thoroughly prepare for this match, and it will be interesting to see how he tactically lines up here.
United will likely field a similar team to the first leg—a strong backline with extra help on Ronaldo, wingers who will sit quite high, a central midfielder or midfield paring and their attacking line of Rooney and Van Persie—but Madrid's is not so guaranteed.
Will Mourinho play a man on Rooney like Sir Alex Ferguson will Ronaldo? Does Raphael Varane pick up Van Persie or Rooney when the Red Devils attack? Will Angel Di Maria feature more centrally for Los Blancos here and Mesut Ozil out wide, or will they play their more regulation positions?
Whatever the answers to those questions are, it is clear that Mourinho holds the balance of power tactically here in his ability to change things up a bit.
If United are going to play a man on Ronaldo—which it seems they have to—then Ferguson is limited in terms of the tactics he can employ. That does not to apply to Mourinho as much, who will have the liberty to explore the best alternatives to stopping the Red Devils' attack.
And if that can happen, Madrid will seemingly be very close to victory.
What key questions do you think will come up in this UCL clash?
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