Holders Barca drew 0-0 in Milan in the first match last week and Pep Guardiola's side remain favorites to advance but a score draw for the Serie A champions on Tuesday would cause a right royal upset.
Fellow European gentry Bayern will be highly confident of progressing on Tuesday against Olympique Marseille having won 2-0 in France last week while possible semi-final opponents Real welcome APOEL Nicosia on Wednesday holding a 3-0 lead.
Chelsea are 1-0 up with a home game to come against Benfica on Wednesday and the London team's improvement under interim coach Roberto Di Matteo, with even Fernando Torres creating and scoring goals, suggests they ought to go through.
Most eyes are therefore focused on the Nou Camp where Barca — lauded by many pundits as the greatest club side of all — take on seven-times European champions Milan and former striker Zlatan Ibrahimovic.
Milan looked like the away side for much of last week's game at the San Siro but they kept Barca and World Player of the Year Lionel Messi at bay while also going close through Ibrahimovic and Brazilian Robinho.
"It is the most important match of the year and at the same time the most beautiful one," Guardiola told reporters after a 2-0 home win over Athletic Bilbao in La Liga at the weekend.
"Bilbao don't defend, they come at you. It's completely different from Milan, it's like night and day." Milan boss Massimiliano Allegri vowed to attack Barca last week but it did not turn out that way as the old Italian defensive traits shone through.
He said they should go for goals in the second leg and with the prospect of Barca drawing a blank in two straight Champions League games unthinkable, Allegri's assertion makes sense if his side listen to him this time and do not try for a 0-0 result and penalties.
Sweden striker Ibrahimovic would dearly love to score at the Nou Camp and eliminate his former team having left Barca under a cloud 18 months ago when falling out with Guardiola.
Torres looked to have fallen out with football after an extended spell of poor form but he expertly set up Salomon Kalou for the winner at Benfica and then scored in the weekend Premier League triumph at Aston Villa.
The Spaniard hopes to keep his place on Wednesday with Didier Drogba troubled by a foot problem. Former Benfica defender David Luiz is also a doubt.
Benfica must believe they can turn the tie around but Marseille and Cypriot underdogs APOEL, overwhelmed just to have reached this stage, are ready to kiss the competition goodnight.
Didier Deschamps's Marseille performed a near-miracle in making the knockout stages thanks to a late goal in their 3-2 victory at Borussia Dortmund, their second group win over the Bundesliga champions.
However, the last 16 conquerors of 2010 winners Inter Milan face a seemingly impossible task against another German side given they need to win 3-0 at Bayern who are in fine form thanks to the recent brilliance of Mario Gomez and Arjen Robben.
Jupp Heynckes's side are also desperate to reach May's final in their own stadium.
