Liverpool and Tottenham have been drawn against Zenit St Petersburg and Lyon in what were two of the stand-out ties of the draw for the last 32 of the Europa League.
Meanwhile Newcastle play Ukrainian side Metalist Kharkiv and Chelsea face Sparta Prague.
The path for Tottenham looks particularly tough. Lyon are currently equal on points with PSG at the top of the Ligue 1 table. Should they negotiate their way past the French side, they will then play either Inter Milan or Cluj.
"It's a tough draw and this is the first time in nine years they've not been in the Champions League," Tottenham general secretary Darren Eales told Sky Sports News.
"There are a lot of tough teams in the draw. We can ask Hugo (Lloris, Tottenham's former Lyon goalkeeper) the way to go and I think he will be excited about the chance to go back to his old team and play there.
"If we do get Inter if we do get through, two years ago in the Champions League when Gareth Bale got that wonderful hat-trick - that's an exciting game but we have to think about Lyon first."
And Eales believes Villas-Boas has what it takes to lead Spurs to the European title after he engineered a win for former club Porto during a treble-winning first season in charge which saw his side also lift the Portuguese Cup and win the Primeira Liga.
"He's got the pedigree so hopefully he can do what he did with Porto two years ago and we can go al the way to (the final in) Amsterdam," he said.
"We want to be playing in European competition. We don't see why we can't have a successful Europa League campaign and do well in the league."
Liverpool face a daunting trip to St Petersburg to take on Zenit - a side whose supporters recently requested that black and homosexual players be officially banned from playing for the club. However, if they make their way past the Russians a match against either Basel or Dniprov looks negotiable.
Chelsea, who failed to make the knockout stages of the top-tier European competition, will start their bid to become only the fourth club after Juventus, Ajax and Bayern Munich to win all of the major European trophies. They take on Sparta Prague in what promises to be a fun trip to the Czech Republic for their fans. Should they make it through they will play either Ajax or Steaua Bucharest.
Newcastle face a task advancing to the last 16, playing Ukrainian side Metalist Kharkiv. They have been the Ukrainian champions six years in a row - dating back to 2007. Kharkic finished top of their Europa League group which also included Leverkusen, Rosenborg and Rapid Vienna, losing just once.
Newcastle boss Alan Pardew admitted the club's Europa League adventure in Ukraine will be a trip into the dark.
The Magpies, who were paired with Metalist Kharkiv, face a lengthy journey as well as a tough tie when the competition resumes in February.
Asked what he knew about their next opponents, Pardew said: "Not much, really.
"I do know it's a long journey, I've had a look at that, and they won their group, so it's a tough agenda for us.
"It's a tough draw in terms of travel; the opposition, I know very little about. I can't even comment on that until such time as we do some studying."
Atletico drew Russian side Rubin Kazan as they bid to defend the title they won with a comprehensive 3-0 defeat of Athletic Bilbao in last year's all-Spanish final.
In the other games, Champions League dropouts BATE Borisov face Turkey's Fenerbahce while Spain's Levante take on Olympiacos and Dynamo Kyiv take on Ligue 1's Bordeaux in their knockout ties.
Dutch champions Ajax host Steaua Bucharest first in their round of 32 tie while Germany's Stuttgart host Genk and Bayer Leverkusen play Portugal's Benfica.
Borussia Monchengladbach face Lazio while Swiss champions Basle play Dnipro of the Ukraine, Russia's Anzhi play Hannover and Napoli take on Viktoria Plzen.
Follow the latest reaction to the draw on The Independent's live blog.
Draw for the last 32 and 16 of the Europa League...
Napoli or Viktoria Plzen v BATE Borisov or Fenerbache
Leverkusen or Benfica v Dynamo Kiev or Bordeaux
Anzhi Makhachkala or Hannover v Newcastle or Metalist Kharkiv
Stuttgart or Genk v Monchengladbach or Lazio
Tottenham or Lyon v Inter Milan or Cluj
Levante or Olympiakos v Atletico Madrid or Rubin Kazan
Basel or Dniprov v Zenit St Petersburg or Liverpool
Ajax or Steaua Bucharest v Sparta Prague or Chelsea