After their stunning 4-1 win at home last week, Jurgen Klopp's Borussia Dortmund side are set fair for a place in the Champions League final going in to the return leg at Real Madrid.
But Jose Mourinho's team are unlikely to go down without a fight and will be looking to avenge their humbling. Here, we assess where the game will be won and lost.
PEPE v ROBERT LEWANDOWSKI
There is no doubt as to who had the better of this encounter in Dortmund, with Poland striker Lewandowski bagging four goals, including a second-half hat-trick.
It was a masterclass in clinical finishing but Pepe, as Real's senior centre-half, will be disappointed not to have bossed the penalty area better.
He will look to assert himself at the Bernabeu but Lewandowski will be waiting to pounce should he fail.
XABI ALONSO v MARIO GOTZE
Klopp has spoken in the past about how important keeping Alonso in check is when facing Real and in Gotze he has just the man to do the job.
Gotze's movement and ability to unlock defences left Alonso in a more defensive mindset than he is used to, by turn negating a player Real look to to initiate many of their attacks.
Chasing a three-goal deficit, Alonso may have to focus on playing his own game and shift responsibility for Gotze elsewhere.
CRISTIANO RONALDO v MATS HUMMELS
If anybody is going to inspire Real to an unlikely comeback then a man with 48 goals in 51 games for club and country seems the most obvious candidate.
Ronaldo is capable of shredding opponents when the mood takes him and is capable of doing just about everything imaginable in the final third.
Hummels was at fault for Ronaldo's goal last time out but at his best provides a robust physical presence at the back and is Dortmund's most accomplished defender.