Having been kept apart in the draw for the Champions League quarter-finals, Barcelona and Real Madrid will this week embark on a path that could lead to an all-Spanish showdown in the final in Munich on May 19.
Rampant in La Liga, where the top two enjoy a 22-point cushion over third-placed Valencia, Barca and Madrid are widely regarded as the two strongest sides in the European game.
Barca got the better of their eternal rivals in last season's semi-finals, before going on to beat Manchester United in the final, but Madrid have redressed the balance this season and currently lead the Catalans by six points in La Liga.
Jose Mourinho's side also benefited from a kinder draw in the Champions League, which paired them with Cypriot minnows APOEL.
The side from Nicosia became the first team from Cyprus to reach the quarter-finals when they beat Lyon on penalties in the last 16 and Tuesday's home leg in the Cypriot capital will be the biggest game in the country's football history.
Following consecutive 1-1 draws with Malaga and Villarreal that had given Barca a glimmer of hope in the Spanish title race, Madrid got their league campaign back on track on Saturday with a 5-1 demolition of Real Sociedad.
Cristiano Ronaldo claimed a brace to take his tally to 101 goals in 92 league appearances, but Madrid's players and staff blanked the media afterwards in protest at the red cards shown to Mourinho, Sergio Ramos and Mesut Ozil at Villarreal.
It was left to former Madrid star Emilio Butragueno, now a club director, to face the press, and he was keen to underline the challenge that APOEL's compact GSP Stadium will present.
"People in Cyprus experience matches as something unique," he said.
"The crowd there is very passionate and we'll have to watch out. I hope we earn a good result there.
"We deserved to win against Malaga and the match against Villarreal was somewhat strange, but it's in the past now and we shouldn't think about it. We must concentrate on the European Cup."
Tuesday's other game sees Chelsea visit two-time champions Benfica, who are appearing in the last eight for the first time since 2006.
Benfica beat Zenit Saint Petersburg 4-3 on aggregate in the previous round, but conceded the initiative in the Portuguese Liga title race to Porto following a 0-0 draw at Olhanense on Friday.
Chelsea have been much improved under interim coach Roberto Di Matteo, having overturned a 3-1 deficit to edge Napoli in the last 16 following the dismissal of Andre Villas-Boas.
While the draw was kind to Madrid, Barcelona find their route to the semi-finals blocked by seven-time champions AC Milan.
The sides crossed swords in the group phase, with Milan drawing 2-2 at Camp Nou before falling 3-2 in the return game, and Milan coach Massimiliano Allegri says Wednesday's first leg in Milan will require a thoughtful approach.
"There are two ways to play against Barcelona," he said.
"You either sit deep and hit them on the break, which is difficult, or you go for it like we did in our return match against them, when we made some mistakes."
Milan maintained their stranglehold on the Serie A title race by beating Roma 2-1 on Saturday, while Pep Guardiola's Barca registered their seventh straight La Liga success with a 2-0 victory at Real Mallorca.
With Lionel Messi in irrepressible form, Barca have produced some dazzling performances in recent weeks -- most memorably in the 7-1 demolition of Bayer Leverkusen in the previous round, in which Messi scored five times.
The remaining game on Wednesday pits together two sides whose recent form could not be more contrasting.
Bayern Munich visit Marseille having won their last five games in all competitions, notably scoring 20 goals in three one-sided wins over Hoffenheim (7-1), FC Basel (7-0) and Hertha Berlin (6-0) in mid-March.
Marseille, meanwhile, have seen their hopes of qualifying for next season's Champions League all but dashed by a run of seven straight defeats that finally ended with a 1-1 draw at Nice on Saturday.