Games like this are Rooney's forte. He thrives on the big stage. With all the talk about Cristiano Ronaldo and Robin van Persie in the buildup to this encounter, Rooney will be doubly keen to prove he belongs in the company of the aforementioned stars.
The upturn in Rooney's form recently has gone somewhat unnoticed.
Van Persie has grabbed a large portion of the plaudits with his goalscoring exploits, but Rooney has found the net just as frequently as his Dutch counterpart since the turn of the year. This influx of goals can only mean good things for those of a red persuasion, as Mourinho and Ronaldo loom large.
Rooney will play a more significant role than any of United's players if they are to triumph in the Bernabeu because he has to be involved in all areas of a winning performance.
His versatility will prove significant in all areas of the pitch for United. With Van Persie likely to play at the head of United's attack, Rooney will often drop off to make a five-man midfield. His job will be to stop Xabi Alonso dictating things from deep. Alex Ferguson will expect Rooney to hassle and harry the Spanish pass-master for long spells.
If United and particularly Rooney can stop Alonso from managing the game then their chances will increase markedly. An out-of-sorts and out-of-shape Rooney was asked to do a similar job on Andrea Pirlo for England in last summer's European Championships. He didn't do it well, but should have learnt from that experience.
With Phil Jones likely to vacate central areas and track the runs of Ronaldo, Rooney will have to plug a lot of those gaps in the middle. Madrid are devastating on the break, and if holes start to appear then they will exploited.
Ferguson will be after a titanic shift from his No. 10, but Rooney has shown countless that he is more than capable of putting in the grafting, workman-like performances. In that respect, he is a manager's dream.
What separates Rooney from a lot of players is how he combines this infectious work-rate with his spell-binding ability.
You get the impression that United are going to have to score tomorrow night if they are to progress in the tie. The team that will most likely take to the pitch will be compromised of its usual creativity in favour of industry and work ethic.
Therefore, Rooney must provide an attacking threat for United. If Van Persie becomes isolated, United could be in for a long evening. Rooney is more than adept at picking his forward bursts, but maintaining that link between the midfield and Van Persie will be key if United are going to offer an offensive threat.
Rooney has shown time and time again he is a big-game player. So expect Wednesday night to be no different.
Who do you think will be the key men in Wednesday's clash? Let me know in the comments section or on Twitter: @MattJFootball