Chelsea and Arsenal must both pass Italian tests in the last 16 of the Champions League after the draw in Nyon.
The London clubs are the last remaining Barclays Premier League sides in the competition following the exits of Manchester United and Manchester City in the group phase.
But managers Andre Villas-Boas and Arsene Wenger must overcome Serie A opponents if they are to reach the quarter-final stage, with Chelsea drawing Napoli and the Gunners landing AC Milan.
Napoli were responsible for City's exit after taking four points off Roberto Mancini's side in Group A and their forward pairing of Edinson Cavani and Ezequiel Lavezzi is one of the most feared in Europe.
As group winners both English sides will play away in the first leg, which takes place on 14/15 or 21/22 February, before the return fixtures on 6/7 and 13/15 March.
Chelsea secretary David Barnard admitted Napoli represented a tough draw for the Blues.
"It will be difficult having seen Napoli when they were in the same group as Man City," he said.
"Unfortunately City are no longer with us which reflects the quality of Napoli."
While Chelsea have never before met Napoli in European competition, they are not an unknown threat for boss Villas-Boas after he worked under Jose Mourinho at Inter Milan.
"It's a new experience for us with this club," Barnard added.
"Andre has experience in Italy though from when he was with Inter so he know the ins and outs of Napoli."
Napoli are eager to prove they belong in the Champions League.
"It's not possible to say whether our tie is difficult or easy," Napoli president Aurelio De Laurentiis told Gazzetta dello Sport. "Chelsea is a very strong team but so is Napoli. We are an international team.
"Of course other teams have been more fortunate than us but we are nevertheless happy with the draw."
De Laurentiis believes the challenge for his side will be to control the nerves.
"It's going to be very interesting. My players need to know how to dominate emotions but I'm certain they will bring out their best."
Arsenal club secretary David Miles was upbeat about the testing draw, highlighting his side's impressive record against Italian opposition and declaring it the "pick of the round".
"There were probably other teams we would have preferred but the last time we played them in the knockout stage, in '07-08, we actually went through and won 2-0 in the San Siro," he said.
"We also knocked out, in fairly recent history, Roma and Inter Milan. It's going to be tough. Everyone has earned the right to get to this stage but nevertheless, we're confident and it's going to be two great games.
"I would guess it's probably the pick of the round."
Milan coach Massimiliano Allegri told Gazzetta dello Sport: "It's not a question of revenge. We know Arsenal, it's a team that plays well.
"We will have to arrive in February in the best possible condition and without injuries."
Allegri, whose team finished second in Group H behind holders Barcelona, is aware his players will have to step up their game if they are to go far in the competition.
The Rossoneri won just two of their pool games and have not won on the road in Europe this season - they were held to a 1-1 draw at Bate Borisov and ended the group phase with a 2-2 draw at Viktoria Plzen.
"We will only concentrate in the Champions League in February," Allegri said.
"If we make the same mistakes as we did in Prague and in Minsk, it will be difficult to progress."
Elsewhere, Barcelona face Bayer Leverkusen and the holders, who have advanced to the final of the FIFA Club World Cup in Japan, will be confident of progressing against a side currently sixth in the German Bundesliga.
Thei president Sandro Rosell said: "When you reach the last 16 we have to be ready to face any opponent, and as such we would have been happy with whatever team we got. Every team has its pros and cons.
"For example the Russian teams, we would have preferred not to have faced them due to the plane trip, having to travel a day before, and for the cold, but then they are in pre-season."
Their arch-rivals Real Madrid pulled out CSKA Moscow and director Emilio Butragueno, a director of nine-time European champions Real Madrid, said: "They are a dangerous team and they showed that by knocking out Lille, last season's French champions, and beating Inter in Milan. In football you never know. They have good, young and fast players."
Madrid will also have to contend with the conditions in Moscow and the artificial pitch at the Luzhniki stadium when they make the trip to the Russian capital.
The former Madrid legend added on his club's website: "We must be wary because we will play the first leg in February and we will find a low temperature in Moscow.
"We need to take it game by game because a bad night could leave you out of the competition. We have a great team and this season the performance of our players has been very good."
Bayern Munich, who host the final, were paired with Basle while 2010 champions Inter Milan will face Marseille.
And Inter coach Claudio Ranieri is relishing the chance to pit his wits against Didier Deschamps.
"It will be a nice challenge with Deschamps," Ranieri told Gazzetta dello Sport. "He already knocked me out of the competition in 2004 when I was at Chelsea and he was in charge of Monaco. I hope it goes better for me this time around."
Ranieri, who replaced Deschamps at Juventus in 2007, insists his side will not take the French giants lightly.
"I cannot say whether it is a positive draw or not," he said.
"I will be able to say that I'm satisfied after we have played those two games.
"The name of the opponent doesn't really matter. I've already told my players this. We just have to think about ourselves and prepare for these games in the best way possible.
"I just hope that we get to February in good form and with my players in good physical shape."
Zenit Petersburg take on Benfica and Lyon were pulled out against last 16 surprises APOEL Nicosia.
UEFA Champions League Round of 16 Draw is as follows:
Lyon v APOEL
Napoli v Chelsea
AC Milan v Arsenal
Basel v Bayern Munich
Bayer Leverkusen v Barcelona
CSKA Moscow v Real Madrid
Zenit St Petersburg v Benfica
Marseille v Inter Milan
First leg matches will be played on 14/15 and 21/22 February. Second leg matches will be played on 6/7 and 13/14 March.
More to follow...
