Atletico Madrid will look to put its patchy home form in the shade with a UEFA Europa League quarter-final first-leg win against Hanover on Friday (AEDT) that could put it 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 hosts Valencia, Athletic Bilbao is away to Schalke 04 and Sporting Lisbon hosts Ukraine's Metalist Kharkiv.
Atletico, the inaugural winner of the competition in 2010, has 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 European football next season.
Defender Juanfran Torres said the Rojiblancos are desperate to get back to winning ways.
"The objective is Thursday," Juanfran told Spanish daily Marca.
"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."
Hanover is the least experienced side in the competition but coach Mirko Slomka can boast of having taken Schalke to the semi-finals of the 2005-2006 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.
This year Atletico could meet Valencia in the semi-finals, if its Spanish league neighbour overcomes AZ over two legs to take what would be its second Dutch scalp in succession after the 5-3 aggregate win over PSV Eindhoven.
Valencia's last European triumph goes back to 2004 when it beat Marseille 2-0 to win the UEFA Cup.
On Friday the Spaniards will be without French central defender Adil Rami, who sits out a one-match ban after 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 its deserved elimination of Manchester United, Athletic must raise its game again to face a Schalke team which scored a 4-1 win at bottom-side Kaiserslautern on Monday.
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 UEFA Champions League spot next season.
Athletic defender Javi Martinez has urged his teammates 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.
UEFA Europa League
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