Champions League favourites Barcelona face an all-Iberian derby with Benfica while AC Milan continue their long road back to the final at Olympique Lyon when the quarter-final first legs kick off this week.
Juventus, beaten by Milan on penalties in the 2003 final, take their hopes to Highbury, while Inter have the least intimidating game on paper at home to Villarreal.
Inspired by Brazil forward Ronaldinho and Cameroon striker Samuel Eto'o, but missing injured Argentina playmaker Lionel Messi, Barcelona will look to inflict the kind of away-goals damage on Benfica that paid dividends against Chelsea.
Eto'o's winner in last month's 2-1 victory at Stamford Bridge proved decisive, setting the big-spending Premier League club too big a task in the second leg at the Nou Camp.
Both sides will be counting the absentees, with Benfica missing the Portuguese league's top scorer Nuno Gomes through suspension and Barca being without defenders Rafael Marquez, Edmilson and Carles Puyol through injury and suspension.
Milan, haunted by their dramatic defeat on penalties to Liverpool after leading 3-0 in last season's final, have enjoyed a fine run of form ahead of what will be a tough game in Lyon.
Ukraine striker Andriy Shevchenko and Filippo Inzaghi are expected to spearhead the attack at the Stade Gerland on Wednesday, supported by gifted Brazil playmaker Kaka.
FIRED UP
"The team are really fired up, really motivated," Kaka told Milan's TV channel on Sunday. "We've got great faith in our abilities because we've been playing some really good football.
"Against Lyon, we've got the chance to keep that going."
Their chances of coming away with a decent result will be improved by a one-match ban for the Lyon player Kaka is keeping out of the Brazil side, Juninho, an inspirational playmaker and free kick taker for the four-times French champions.
"We want to reach the semi-finals and this is the match we have been waiting a very long time for," Lyon president Jean-Michel Aulas told the club's Web site on Sunday.
"We're used to getting to the quarter-finals and so far we've never managed to get any further...this is going to be a real test."
Arsenal face a very different kind of examination against Juventus at Highbury when they face their former captain Patrick Vieira, who swapped north London for Turin last year.
Though the French midfielder's absence has clearly been felt, this is a chance for Arsene Wenger's side to emerge from Vieira's shadow and show they can succeed without him.
Juve, who lost 3-1 at Highbury in a group game in 2001, will be without Czech midfielder Pavel Nedved and striker Alessandro Del Piero through suspension and injury respectively.
Serie A rivals Inter will need to show their spark against a determined Villarreal side who have yet to lose in their first season in Europe's flagship competition.
"Clubs who don't have a big name often get underestimated," Inter's Argentine midfielder Esteban Cambiasso told Inter's Web site on Sunday.
"But we'll always respect our opponents and play our game -- whether we're taking on Villarreal or Juventus or AC Milan. Villarreal are dangerous and we know it won't be easy."