With their domestic titles seemingly wrapped up during the two-month Champions League break, Barcelona and Bayern Munich now have the luxury of focusing on winning a fifth European Cup.
Bayern Munich, 15 points clear in the Bundesliga, opens the knockout phase at Arsenal on Tuesday, while the first chapter in another blockbuster Barcelona-AC Milan clash is the following night in the last 16.
Barca have been impervious in Spain, surging 13 points clear in the title race thanks to Lionel Messi remaining in unstoppable form with 48 goals in all competitions this season. The Argentina striker took his club tally to 301 in Saturday's 2-1 victory over Granada before the trip to Milan where he scored twice in last season's quarterfinal triumph.
"It will be a complicated match because we face a very good rival," Barcelona midfielder Cesc Fabregas said. "But we are highly motivated and confident."
While Barcelona is in an enviable position in La Liga, seven-time European champion Milan is 11 points behind Juventus in the Serie A title race.
But Milan has forced its way back into contention for third place by losing just once in its past 13 league matches.
Mario Balotelli has netted four goals in three matches since his tumultuous Manchester City career ended last month, but the Italy striker will be cup tied as Milan looks to end a seven-game winless run against Barca.
"Even if we are the underdogs, we believe in ourselves, we want to do well," Milan defender Philippe Mexes said. "Playing against such a club gives us an extra motivation."
Stephan El Shaarawy has been Milan's most prolific and active player this season, with more than 2,000 minutes of game time yielding 17 goals.
The 20-year-old striker, who was rested against Parma on Friday, underscores the generational change at Milan, with young players being brought through the team.
"Our squad is very young in comparison to last season when we had experienced players such as (Zlatan) Ibrahimovic, Thiago Silva, (Alessandro) Nesta, (Clarence) Seedorf," Mexes said. "Now it's a different Milan but it will always be Milan."
If Milan sees Barca as a daunting opponent, they will be thankful to have avoided Bayern, which is yet to concede a goal in 2013.
Instead Arsenal must take on Jupp Heynckes' side, which was beaten in last season's final by another London club, Chelsea.
"Bayern will be a tough game, but we are confident that on our day we can give anybody a good match," Arsenal midfielder Aaron Ramsey said. "We will all have to be switched on."
Yet Arsenal has never won Europe's top club competition and is enduring a trophy drought stretching back to 2005.