Tottenham, Liverpool and Manchester United all face the prospect of a packed fixture list as they juggle Premier League, FA Cup and Europa League commitments over the next two weeks.
Spurs' title challenge resumes at Aston Villa on Sunday but they face a quick turnaround following their midweek trip to Dortmund.
Meanwhile, Liverpool and United have less distance to travel but the two clubs' rivalry all but guarantees an intense atmosphere across the two legs.
The Europa League last 16 gets under way just as the Premier League approaches the business end of the season, with Tottenham particularly well positioned for a title push, so is playing in Europe's second-tier competition likely to affect league form?
We take a look at recent results after Europa League last-16 action to find out...
2010/11 season
Liverpool were fortunate to avoid a game in between the two legs of their last-16 meeting with Portuguese side Braga in 2011, and the Reds made the use of the extra rest when they dispatched Sunderland 2-0 in their subsequent Premier League match.
Manchester City were slightly less lucky, because while they beat Reading to progress in the FA Cup after a long trip to Dynamo Kiev, a game they lost 2-0, they then lost by the same scoreline at Stamford Bridge three days after elimination by Kiev in the second leg.
2011/12 season
The Europa League took a backseat to the Premier League for City the next year too, but it still threatened to harm their bid for a first top-flight title since 1968.
In between their two legs against Sporting Lisbon, City lost to mid-table Swansea, but after the Portuguese side eliminated them in the second leg, the eventual title winners bounced back with a narrow win over Chelsea.
United also bowed out at the last-16 stage, losing to Athletic Bilbao, but they showed no ill effects with two wins over West Brom and Wolves, scoring seven and conceding none in the process.
2012/13 season
All three English clubs progressed from the last 16 in the 2012/13 season, but only Chelsea escaped without dropped points in the Premier League.
The Blues went on to win the Europa League under Rafa Benitez, and kept up the fight on three fronts as they forced an FA Cup replay against Manchester United in between their games against Steaua Bucharest, before beating West Ham comfortably after the second leg.
Newcastle faced the longest trip as they saw off Russian side Anzhi Makhachkala, but while they beat Stoke 2-1 after the first leg, their follow-up match at Wigan ended in a disappointing 2-1 defeat.
But Tottenham suffered the most as a keenly-contested tie against Inter Milan had repercussions for their league form. After beating the Italians at White Hart Lane, they lost at Liverpool, and after squeaking through on away goals after the second leg in Milan, they lost 1-0 at home to Fulham.
In the end, they missed out on the top four by one point.
2013/14 season
Just the one English team made it through to the last 16, and even then, Spurs could not get past Benfica as they lost 5-3 on aggregate.
The north London derby separated the two legs, and Arsenal took advantage with a 1-0 win at White Hart Lane, but Tottenham followed up the second-leg visit to Portugal with a 3-2 victory over Southampton.
2014/15 season
It was the same story again, as the Premier League's sole representative crashed out at last-16 stage in 2015. Everton could not get past Dynamo Kiev, but had no problem with Newcastle, beating them 3-0 at Goodison Park, before taking three points from QPR at Loftus Road three days after a 5-2 defeat in Ukraine.
So how's it looking for the English sides this year?
Liverpool's meeting with Chelsea, scheduled for Sunday, has been postponed because of FA Cup fixtures, and as a result, the Reds have a week off between the two legs before a trip to Southampton. Considering their last-16 tie is just down the road, they should be well rested.
As for their European opponents, United have three days before they host West Ham in the FA Cup, but the real test won't come until after the second leg, as they travel to the Etihad on March 20.
Finally, title-challenging Tottenham have potentially the most to lose, and they head to bottom-of-the-table Aston Villa on three days' rest before back-to-back home games against Dortmund and Bournemouth.
When they've had big last-16 ties in the past, against Inter in 2013 and Benfica in 2014, they've won just one of the subsequent four games, but with Leicester five points clear at the top, Mauricio Pochettino's side can't afford that kind of run.