Napoli must overturn a 1-0 deficit against Villarreal if they are to keep alive their hopes of exorcising the demons of last season's Europa League semi-final loss.
Denis Suarez's late goal gave Marcelino's side the first-leg honours in their last-32 tie, with Napoli facing a premature exit compared to their last-four defeat against Dnipro in 2014-15.
But captain Marek Hamsik insists there is everything to play for at the San Paolo on Thursday as Napoli seek their first continental title since 1999.
"It's a shame that, again, we conceded a goal right at the end," he told Sky Sport Italia. "A goal really would've helped us for the second leg, but we can still turn this result around."
Manchester United face a battle to keep their own European campaign alive when they host Midtjylland, who recorded a stunning 2-1 victory in Denmark last week to pile more pressure on under-fire manager Louis van Gaal.
United's injury crisis worsened when David de Gea was struck down in the warm-up for that game and, with an FA Cup clash against Shrewsbury Town on Monday, this could prove a defining week in the Dutchman's career at Old Trafford.
Porto face a more difficult task as they attempt to bounce back from a 2-0 defeat to Borussia Dortmund in Germany, while Portuguese rivals Sporting CP must win away to Bayer Leverkusen if they are to go through.
Gary Neville's Valencia are almost into the last 16 thanks to their 6-0 thrashing of Rapid Vienna, while Athletic Bilbao stand in good stead having beaten Marseille 1-0 away and holders Sevilla take a commanding 3-0 lead to Molde.
Tottenham's tie with Fiorentina is finely poised after Federico Bernardeschi ensured a 1-1 draw in Italy in the first leg, while Jurgen Klopp's Liverpool return to Anfield after a 0-0 draw away to Augsburg.
Lazio head back to Rome after securing a 1-1 draw against Galatasaray, Fenerbahce travel to Russia following a 2-0 win over Locomotiv Moscow, while it is all square between Schalke and Shakhtar Donetsk after their goalless draw in Lviv.
Swiss duo Basel and Sion must wipe out one-goal deficits against Saint-Etienne and Braga, while Krasnodar and Olympiacos will look to bounce back from 1-0 first-leg defeats to Sparta Prague and Anderlecht.