The first-leg meeting between the two teams was surprisingly one-sided, although there were defining moments that made this happen.
Real Madrid had been slightly edging the battle, but the deflected opening goal changed the tie completely.
Three-nil down, Atletico now host their rivals with the mammoth task of trying to turn things around.
Diego Simeone will need to execute a perfect overall strategy, whilst the individual players will need to boss their counterparts.
Diego Costa did the perfect job of upsetting at least three of the defensive five players in Real Madrid's system, but as a consequence, picked up a booking which rules him out of this one.
With David Villa injured, it's likely that Adrian Lopez will lead the line for Atleti, unless Simeone opts for either Arda Turan or Diego as a false nine.
As both Marcelo and Fabio Coentrao were forced to leave the field early against Villarreal, left-back is a problem position for Carlo Ancelotti.
Alvaro Arbeloa is expected to start there, with Dani Carvajal keeping his place on the right of the defence.
Bale played 90 minutes at the weekend, but is he ready to play three games in nine days?
The Italian admitted in his pre-match press conference last Friday, via Football Espana, "He (Jese) has come on a lot and is playing well. But he is still young and we have to be careful with him."
Karim Benzema could be given the evening off, with Isco operating as the sole forward. The jury is still out on his effectiveness in the role, but he would make it harder for Atletico to maintain possession when adding an extra number in midfield.
Juanfran vs. Ronaldo
The Atleti full-back was on the left against Almeria, though he should return to his preferred side with Ronaldo playing.
Juanfran is naturally a winger, but his attacking instincts are curbed when up against the Portuguese forward.
The Spaniard did a good job of neutralising Ronaldo in the first leg and will need to keep him quite again if the team is to advance.
As Ronaldo doesn't track back, then Juanfran will need to be more adventurous and help his winger overload Madrid's left-back.
Insua vs. Jese/Bale
Emiliano Insua had a torrid time against Jese in the first leg, which started with a wicked deflection for Real Madrid's opener.
Simeone opted to give him the weekend off to recover, but it's likely that he will be reinstated once more.
The Argentine left-back is no slouch, though the pace of Jese or Bale will cause him considerable nightmares.
At the age of 25, he is yet to hold down a regular position in any of the teams he has played and fulfil the promise shown when looking to establish himself.
Diego vs. Alonso
Diego returned with a bang against Real Sociedad, as he came off the bench to score Atletico's fourth and final goal.
He struggled with the speed of the match at the Bernabeu, as it was only his second start of the year due to the extended winter break in Germany.
Xabi Alonso was rested versus Villarreal, so he should be ready to exert his influence in this game.
Who pays the closest attention to the other when without the ball could determine the winner in this personalised contest.
Gabi vs. Modric
This is a classic encounter of opposite attributes: tackling vs. passing, tenacity vs. vision and strength vs. movement.
Gabi records the fourth highest tackles per game in the league, whilst Luka Modric has the second highest pass completion percentage if you don't include Barcelona and seventh if you do, via Who Scored.
With Atletico needing to overturn a huge aggregate scoreline, it could be down to their ability to take on the persona of their opponent.
Gabi will need to be incisive with his passing, with Modric having to win the ball back and position himself well to stop the counter-attacking brilliance of Simeone's men.