Holders Inter Milan, 2009 champions Barcelona and last season's semi-finalists Lyon can all reach the last 16 of this season's Champions League with victories in the group stage on Tuesday.
Inter, who ended a 45-year wait for Europe's top club prize in May, face perhaps the most difficult assignment of the three in the shape of a trip to competition debutantes Tottenham in Group A.
The sides shared seven goals when they met in Milan twelve days ago, but despite Inter having led 4-0 after 35 minutes, Spurs emerged from the game with real credit, thanks to a stunning second-half hat-trick by Gareth Bale.
Bale's performance at the San Siro prompted his coach Harry Redknapp to label the 21-year-old Welshman one of the world's top left-sided players, and his late cameo gave Inter boss Rafael Benitez plenty of food for thought.
"The return match in London will be tough," said Benitez, who spent six years at the helm of Spurs' Premier League rivals Liverpool.
"Tottenham are a quality team and despite their bad start they showed what they are capable of in the second half."
Spurs were beaten 2-0 at Manchester United on Saturday, but of more concern to Redknapp will have been a hamstring injury to Rafael van der Vaart that forced the in-form Dutch playmaker to go off in the second half.
Inter have had an extra day to prepare for the match following their 1-0 win at Genoa on Friday, but they could be without goalkeeper Julio Cesar and holding midfielder Esteban Cambiasso after both players sustained thigh strains.
Werder Bremen and FC Twente meet in the other group game in Germany, with both sides conscious that victory would take them into second place if Inter prevail at White Hart Lane.
Barcelona visit FC Copenhagen in Group D, fresh from a stunning 5-0 demolition of Sevilla in the league on Saturday inspired by the return from injury of midfield lynchpin Xavi.
"We're not better than we were before because we've won 5-0, but we are on the right track," tempered Barca midfielder Andres Iniesta, after a game in which both Lionel Messi and David Villa scored twice.
"Tuesday's game is important for our future and we have to play very well."
Lyon brought an end to a turbulent week by beating Sochaux 2-1 at the weekend, after president Jean-Michel Aulas ended weeks of speculation by confirming that Claude Puel will stay on as coach until the end of the season.
The 2002-2008 French champions, eliminated by Bayern Munich in the semi-finals last season, have won all three of their group phase games to date but Tuesday's trip to Benfica will be their most taxing assignment yet.
Pablo Aimar scored a stunning solo goal as the Portuguese champions beat Pacos de Ferreira 2-0 in the league on Friday and Aulas says he would be happy to return from the Stadium of Light with a point.
"A draw in Lisbon and we could start thinking about finishing top of the group," he said. "We definitely can't afford to lose."
In the group's other game, Hapoel Tel-Aviv must win at home to second-placed Schalke to avoid elimination.
Group C leaders Manchester United travel to Turkey to tackle bottom side Bursaspor, having edged the Turkish champions 1-0 in their last outing.
Sir Alex Ferguson's team are yet to concede a goal in this season's competition and victory would give them ten points from four games, taking them to the brink of the knockout phase.
"We are on a run that suggests we have recovered our old tenacity and composure," said Ferguson after the defeat of Spurs at Old Trafford.
Valencia, meanwhile, can leap-frog Rangers into second place if they beat the Scottish champions at the Mestalla.