The German outfit needed two late goals to overcome Malaga in the previous round, while Madrid survived a second-leg comeback from Galatasaray to book their spot in the final four of the competition.
The two sides were paired in the group stages of the Champions League this season, with Dortmund winning the home match 2-1 before gaining a 2-2 draw at the Bernabeu in the beginning of November.
If that pattern of results follows this time around, then Dortmund would advance to the final at Wembley where they would face either Bayern Munich or Barcelona, who clash on Tuesday.
The home side have no fresh injury concerns ahead of the match, although one from Mats Hummels, Felipe Santana and Neven Subotic will miss out in central defence. Nuri Sahin is also expected to gain a start, with Robert Lewandowski and Marco Reus forming the attacking pair.
Alvaro Arbeloa is also struggling, but Fabio Coentrao should be fit to start. Diego Lopez is once more expected to be given the nod ahead of Iker Casillas between the sticks, while Karim Benzema should also start up front.
Dortmund: Weidenfeller; Piszczek, Hummels, Santana, Schmelzer; Blaszczykowski, Gotze, Gundogan, Sahin; Reus, Lewandowski
Madrid: Lopez; Arbeloa; Ramos, Varane, Coentrao; Ozil, Alonso, Khedira; Ronaldo, Benzema, Di Maria
Sports Mole says: 2-2