More accustomed to challenging for Premier and Champions League honours, five-times European winners Liverpool have this season been forced to set their sights on the less glamorous Europa League after an unhappy campaign.
Juventus, also forced to aim lower after a troubled last few months, defend a 3-1 lead at Fulham while Anderlecht's 16-year-old Romelo Lukaku could be the biggest threat to German side Hamburg SV, who take a 3-1 lead to Belgium.
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Buoyed by Lyon, who successfully defended a 1-0 advantage at the Bernabeu to knock Real Madrid out of the Champions League last week, Lille take the same scoreline to Anfield hoping for a similar upset.
"We've taken the lead but we know that we'll have to give everything in an even tougher game," said 19-year-old Eden Hazard, whose fortuitous free kick sealed a first-leg win.
"Hopefully, we can produce the same sort of game Lyon delivered at Real. As for my goal, I'm not supposed to take the free kicks but I was asked to. I wanted to put it in the box. No one touched it. Good for us. We hope we can keep this advantage," he told UEFA.com.
FIGHTING RELEGATION
Premier League underdogs Fulham, fighting relegation only two years ago, host twice European champions Juventus still hopeful they can pull off an upset.
It would not be their first of the campaign having already eliminated titleholders Shakhtar Donetsk in the previous round.
"Coming to places like Craven Cottage is intimidating for teams like Juve," Fulham defender Chris Baird told the club website.
"We're looking forward to the game. We know the threat they're going to pose to us but it's another great game to play in and hopefully we'll get the right result for Fulham."
Anderlecht will look to impressive league topscorer Lukaku to help overturn Hamburg's lead. Already a full international, he has caught the attention of a number of big clubs but intends to stay with the Belgian side until he is 20-years-old.
Three of the ties are drawn at 1-1 after the first leg - Olympique Marseille and Benfica, Werder Bremen and Valencia and German champions VfL Wolfsburg and Rubin Kazan - while Sporting host Atletico Madrid after a goalless first leg.
Belgian side Standard Liege have a healthy 3-1 lead as they host Greek league leaders Panathinaikos.
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