Los Blancos were knocked out in the semi-finals last season thanks to the inspired efforts of the Poland striker but will be confident of sealing a triumph this term
The two sides met at the last-four stage in 2012-13, with a Robert Lewandowski-inspired Dortmund blowing Real away 4-1 in the first leg at home before holding on in the return game to progress to the final despite a 2-0 defeat.
Madrid and Dortmund also went head-to-head in the group stages last season, and once again it was the Germans who came out on top, winning 2-1 at home and earning a 2-2 draw at Santiago Bernabeu.
Dortmund will have to manage without talismanic striker Lewandowski for this week's meeting, however, with the Poland international serving a one-match ban.
Jurgen Klopp's men scraped into the last eight with a 5-4 aggregate success over Zenit, while Real were far more comfortable in seeing off Schalke, brushing aside Dortmund's fierce rivals 9-2 over two legs.
Real have not lost in the Champions League since last year's semi-final first-leg defeat to Dortmund, recording eight wins and a draw in that time and scoring 31 goals in the process.
The Spanish giants are searching for their 10th European Cup success, and first since 2002, with coach Carlo Ancelotti calling on the Bernabeu faithful to inspire his team to victory this week.
"On Wednesday we'll have a great atmosphere at the Bernabeu because everyone is dreaming of the Decima," he said.
"They know we can win if everyone gets behind the team. Together we can achieve the dream."
Ancelotti's men bounced back from successive league defeats to Barcelona and Sevilla with a 5-0 thrashing of Rayo Vallecano on Saturday, with top-scorer Cristiano Ronaldo breaking the deadlock with his 44th goal of the season in all competitions.
The Portuguese is the leading marksman in the Champions League this term, with 13 goals in seven matches, and Dortmund will have to find a way of stopping the deadly attacking trio of Ronaldo, Gareth Bale and Karim Benzema if they are to remain in the tie heading into the return leg.
Klopp's side have been well off the record-breaking pace of champions Bayern Munich in the Bundesliga this season, but the coach refuted suggestions this season's team is worse than the one that reached the final 12 months ago.
"We are on the road to achieving all the goals we set ourselves at the start of the season," he told Marca.
"We're second in the Bundesliga, we're in the DFB-Pokal semi-final and we have made it to the quarter-finals of the Champions League, just like last year."
Dortmund have been hit by a chronic injury crisis this season and will be without the quartet of Neven Subotic and Jakub Blaszczykowski (both knee), Marcel Schmelzer and Sven Bender (both groin) for the trip to the Spanish capital.
Their hosts are not without injury problems of their own, however, with Ancelotti forced to manage without Alvaro Arbeloa, Sami Khedira and Jese Rodriguez (all knee).