Chelsea must repeat last season's Champions League win against Barcelona and Arsenal will have to overcome Real Madrid to reach the quarter-finals.
Mourinho must hope for repeat success against Barcelona
The Premiership duo were drawn to face the Spanish giants in Friday's draw for the last 16 of the Champions League.
Holders Liverpool have been drawn to play Manchester United's conquerors Benfica, while Rangers face a tough test against Villarreal of Spain.
The other big game in the round will be between Bayern Munich and AC Milan.
Chelsea's meeting with Barcelona will evoke memories of last season's controversial encounter in the last 16 of the Champions League.
Jose Mourinho accused Barcelona coach Frank Rijkaard of influencing referee Anders Frisk after a 2-1 defeat in the first leg that saw Chelsea striker Didier Drogba sent off.
Chelsea won 4-2 in the second leg at Stamford Bridge to go through, beating Bayern Munich in the last eight before losing to Liverpool in the semi-final.
But Chelsea chief executive Peter Kenyon is confident last season's row will not overshadow the game.
He said: "We want to put that behind us now. We want to look forward. We had two fantastic games against them last year. Memorable.
"Even in rehearsal we got Barcelona so I didn't think lightning would strike twice.
"But at this stage in the competition you expect to get a big team and we have got one. At the moment they are as hot as we are in the UK."
Real Madrid will present a formidable barrier to Arsenal's hopes of claiming a first Champions League triumph, with England captain David Beckham and possibly Jonathan Woodgate in opposition.
But boss Arsene Wenger will be hoping his side can take advantage of the current turmoil at The Bernabeu after coach Wanderley Luxemburgo's sacking, to send Real crashing out.
Arsenal vice-chairman David Dein was jubilant after the draw, saying: "Pure showbusiness. It's fantastic. It's one of the draws of the round.
"We have never played Real Madrid before in Europe but, of course, they are one of the great teams of Europe.
"Never underestimate Real Madrid because they are one of the very best. I suppose it's what everyone dreams of.
"We would have loved to have played them in the final and we would love to get to Paris, as a lot of our boys know the way there very well. But now we'll have to do it the hard way."
Real's former Manchester United star David Beckham was also thrilled by the prospect of facing the Gunners.
He said: "I have been in Spain for two-and-a-half years and I have never played in England with Real Madrid but I have always wanted to.
"I have got enormous respect for their manager Arsene Wenger. He is not only a great person but also an excellent manager and trainer.
"They have got good players and it will be difficult but I'm looking forward to playing in England.
"Arsenal have got really passionate fans and they're right on top of the team and the pitch. It'll be a good atmosphere but a hard game."
Liverpool will be aiming to fare better against Benfica than Sir Alex Ferguson's side, who went out at the group stage after a 2-1 defeat in The Stadium of Light.
And Liverpool boss Rafael Benitez will be delighted to have the second leg at Anfield by virtue of finishing top of their group.
Rangers will also be reasonably satisfied to have avoided the big guns, but will face a tough test against Spanish dark horses Villarreal.
CHELSEA v Barcelona
Real Madrid v ARSENAL
Werder Bremen v Juventus
Bayern Munich v AC Milan
PSV Eindhoven v Lyon
Ajax v Inter Milan
Benfica v LIVERPOOL
RANGERS v Villarreal
(Ties to be played 21/22 February and 7/8 March)