The other three ties are also delicately poised in a competition which is often dismissed as the poor relation to the Champions League but which this year has featured some outstanding games in the knockout stages.
English side Fulham, playing in the quarter-finals of a European competition for the first time, take a 2-1 lead to German champions VfL Wolfsburg determined to continue a run which has captured the imagination of their supporters.
"We did it the difficult way in Germany and we are capable of repeating that in Madrid," playmaker David Silva told UEFA.com.
"Playing Atletico felt very similar to the first leg against Werder because of the opportunities we didn't convert. The Calderon is a difficult place to try to win, but if we create as many chances as we did in Germany, then we'll do it.
"We will travel with confidence in our ability and we will show pride."
Valencia are hoping for another inspired performance from Spain's World Cup-bound striker David Villa, whose 27 goals in all competitions this season included a stunning hat-trick at Werder and a late equaliser in the first leg against Atletico.
"Our main goal is to win the national championship," Benfica coach Jorge Jesus, whose team will be without former Argentina forward Javier Saviola due to a foot injury, told reporters.
"It is huge what we have already accomplished for the club and as players we want to continue it," said goalkeeper Mark Schwarzer.
"You need to ask the chairman and the fans how big an achievement they think it is, but as players we are on the verge of something huge."
