Cape Town - Manchester United will face Belgian club Anderlecht in the Europa League quarter-finals after Friday's draw in Nyon, which saw France's Lyon land Turkish champions Besiktas.
Jose Mourinho's side are the only English club left in the competition after labouring to a 2-1 aggregate win over Russian side FC Rostov in the last 16.
United are favourites to win the competition for the first time in Solna, Sweden on May 24 which could earn them a passage into next season's Champions League.
It will be the fourth meeting between the sides, with United winning the three previous ones.
Their record European victory was against Anderlecht, a 10-0 rout at Old Trafford in the European Cup preliminary round in 1956.
Spanish sides have won seven of the last eleven second-tier European titles and hopes of further domination rest on Celta Vigo's shoulders as they take on Belgian club Genk.
Two former winners were pitched together as Dutch giants and 1992 champions Ajax face Germany's Schalke 04, who won in 1999, in home and away ties to be played on April 13 and 20.
Schalke's Dutch striker Klass-Jan Huntelaar, formerly of PSV Eindhoven, tweeted "Amsterdam, Amsterdam, Amsterdam," to show his delight at landing his former rivals.
Lyon are seen as second favourites after United to lift the trophy after overcoming Roma and were upbeat despite a tough draw.
"They're a great team and there'll be an amazing atmosphere," said Lyon advisor Bernard Lacombe.
Besiktas director Ali Naibi felt the same way. "Playing the second leg in front of our own crowd will help. Lyon have experienced and talented players, so it'll be difficult," he warned.
Anderlecht v Manchester United
Celta Vigo v Genk
Ajax Amsterdam v Schalke
Lyon v Besiktas