Atletico Madrid will look to put their patchy home form in the shade with a UEFA Europa League quarter-final, first leg win against Hannover on Thursday that could put them within sight of an all-Spanish final.
The other ties feature several teams unused to reaching the latter stages of a European club tournament but presents them with a tantalising prospect of silverware. Unfashionable Dutch side AZ Alkmaar host Valencia, Athletic Bilbao are away to Schalke 04 and Sporting Lisbon host Ukrainians Metalist Kharkiv.
Atletico, inaugural winners of the competition in 2010, have shown solid form in Europe since former Argentina international Diego Simeone took over as coach at the end of the year.
Yet a 1-0 defeat to the Spanish league's bottom side, Real Zaragoza, has left Simeone's side eighth in the table and in danger of missing out on UEFA Champions League football next season.
"Then after that we have Getafe, and from there we go from game to game. We have a lot at stake in the next three games but the team is ready to give it everything."
Hannover are the least experienced side in the competition, but their coach Mirko Slomka can boast of having taken Schalke to the semi-finals of the 2005/06 UEFA Cup. There is also the small issue of hosting first, and the fear of conceding an away goal.
In the 2010 quarter-finals former Atletico striker David Villa scored late to secure a 2-2 draw at Valencia in the first leg, a strike which proved decisive after the second leg finished scoreless. An away goal against Liverpool in the second leg of the semi-final then sent Atletico to the final where they beat Fulham 2-1 after extra time.
Potential for all-Spanish finale
This year Atletico could meet Valencia in the semi-finals, if their Spanish league neighbours overcome AZ Alkmaar over two legs to take what would be their second Dutch scalp in succession after their 5-3 aggregate win over PSV Eindhoven.
Valencia's last European triumph goes back to 2004 when they beat Marseille 2-0 to win the UEFA Cup. On Thursday the Spaniards will be without French central defender Adil Rami, who sits out a one-match ban following a red card against PSV, but they head to Alkmaar fresh from a morale-boosting 3-0 league win over Athletic Bilbao.
Barely two weeks after their deserved elimination of Manchester United, Athletic must raise their game again to face a Schalke team which scored a 4-1 win at bottom-side Kaiserslautern on Sunday. The win was inspired by star strikers Raul and Klaas-Jan Huntelaar and kept Huub Stevens's side in contention for the league title and a Champions League spot next season.
Athletic defender Javi Martinez has urged his team-mates to forget recent setbacks and focus on the job at hand. "We have to maintain the maturity we've demonstrated lately... and show that what we achieved at Old Trafford was no accident," said Martinez.
Awaiting the winners of that tie in the semi-finals will be Sporting Lisbon, or Metalist Kharkiv, who meet for the first leg in Portugal. They have never met in the competition, but Sporting's fans will be boosted knowing the Portuguese have won all four of their previous games against Ukrainian sides in European competition.