Three teams must go to Eastern Europe in February - Liverpool take on Zenit St Petersburg, Chelsea face Sparta Prague and Newcastle have been drawn against Metalist Kharkiv of Ukraine.
Spurs take on Lyon - keeper Hugo Lloris facing his old team-mates - and if they come through that they could face Italian giants Inter Milan in the last 16.
It would be a much-anticipated match and evoke memories of when Gareth Bale scored a hat-trick at the San Siro for Tottenham against Inter in a match that eventually saw the north London side lose 4-3 in October 2010.
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 as they bid to usurp defending champions Atletico Madrid.
If the Blues knock Sparta out, they will face either Ajax or Steaua Bucharest in the last 16.
Former Chelsea midfielder Jiri Jarosik will come up against his former employers after moving back to the Czech capital last year.
Newcastle will fancy their chances against Metalist, one of the smaller clubs left in the draw. If they advance they could then face the hugely wealthy Russian side Anzhi Makhachkala or Bundesliga side Hannover.
Liverpool look to have the hardest draw - Zenit have Brazilian superstar Hulk in their line-up but the Reds will have home advantage in the second leg.
Last 32 draw:
BATE Borisov v Fenerbahce
Inter Milan v Cluj
Levante v Olympiakos
Zenit St. Petersburg v Liverpool
Dynamo Kiev v Bordeaux
Bayer Leverkusen v Benfica
Newcastle v Metalist Kharkiv
Stuttgart v Genk
Atletico Madrid v Rubin Kazan
Ajax v Steaua Bucharest
Basel v Dnipro Dnipropetrovsk
Anzhi Makhachkala v Hannover
Sparta Prague v Chelsea
Borussia Moenchengladbach v Lazio
Tottenham v Lyon
Napoli v Viktoria Plzen
First-leg matches are played on February 14, and return games on February 21.
Napoli or Viktoria Plzen v BATE Borisov or Fenerbahce
Bayer Leverkusen or Benfica v Dynamo Kiev or Bordeaux
Anzhi Makhachkala or Hannover v Newcastle or Metalist Kharkiv
Stuttgart or Genk v Borussia Moenchengladbach or Lazio
Tottenham or Lyon v Inter Milan or Cluj
Levante or Olympiakos v Atletico Madrid or Rubin Kazan
Basel or Dnipro Dnipropetrovsk v Zenit St. Petersburg or Liverpool
Ajax or Steaua Bucharest v Sparta Prague or Chelsea