Juergen Klopp and Jose Mourinho have already met twice this season, and BVB fans will be hoping their manager can overcome the odds once again to lead them into the final.
Here are five tactical factors to consider before and during the game.
We're seeing a rising trend in world football: advanced playmakers taking on disruptive roles, man-marking deep-lying playmakers and preventing them from dictating in space.
Bayern Munich nullified Andrea Pirlo in the UEFA Champions League quarterfinal and Xabi Alonso has received similar treatment from an array of opposing teams.
He doesn't have the pace to get away from his marker, and Borussia Dortmund could look to cut out Real Madrid's primary creative threat by deploying someone on him.
But in the same vein, Ilkay Gundogan received some very special attention from Duda in Dortmund's tussle with Malaga—combined with the absence of Mats Hummels, it prevented Dortmund from playing out properly from the back.
Could Madrid fight fire with fire?
How will Borussia Dortmund deal with Cristiano Ronaldo?
These two sides have met before, and—perhaps most interestingly—both Juergen Klopp and Jose Mourinho are renowned for their ability to "figure the opposition out" after a first encounter.
Cristiano Ronaldo was limited against BVB in the group stages, but that was largely down to the injuries los Blancos had sustained at full-back.
With Michael Essien ineptly filling in on the left, there was no overlapping man to detract markers and let Ronaldo inside—Lukasz Piszczek and Sebastian Kehl did a two-man job of marking him out of the game.
With both Marcelo and Fabio Coentrao in contention, will things be rather different?
Borussia Dortmund defender Mats Hummels has spoken ahead of the clash, suggesting possession will be key to winning (via Goal.com):
Ball possession will be a key factor against Real Madrid.
I remember our match at the Santiago Bernabeu during the group stage. In the second half we did not have the ball for longer than ten seconds before we lost it again, and then it is really difficult against them.
The thing is, Real Madrid are pretty happy without the ball, so for BVB to go out and intentionally monopolise possession would play into their hands.
Ilkay Gundogan and Hummels will be key in orchestrating, but will also need to be mindful of explosive counterattacks.
Everything Real Madrid do on the football pitch revolves around one common goal: create space for Cristiano Ronaldo.
Whether that's a long punt over the top for him to run onto or a searching run from Marcelo to take away markers, the Portuguese forward is at the centre of every move.
Borussia Dortmund won the home fixture in the group stages 2-1, and Madrid's solitary goal came from a ball over the top for Ronaldo to chase and finish.
Juergen Klopp will look to Lukasz Pisczcek to get involved in the attacking phases—he's one of the better attacking right-backs in world football—but no one will envy the mindful job he'll have to do on his marker at the other end of the pitch.
Finally, Borussia Dortmund's attacking fortunes largely hinge upon one critical factor: whether or not they can overcome Real Madrid's double pivot in midfield.
Sami Khedira and Xabi Alonso have formed an incredible duo in front of Jose Mourinho's defensive line, shielding them to the point where the side becomes borderline impregnable at times.
It's stood the test against the vivacious attacking forces of Barcelona, so Mario Goetze, Marco Reus and Robert Lewandowski will do very well to find a way around it.
Lukasz Piszczek coming forward down the right and feeding Lewandowski looks a strong option, while Hummels' direct delivery from centre-back will also be important.
Khedira and Alonso are several steps up from Jeremy Toulalan and Ignacio Camacho, so Juergen Klopp needs to get his thinking cap on.