Jose Mourinho's return to the San Siro will highlight Wednesday's Champions League action which could see his Real Madrid advance to the last 16 with a win over AC Milan as Arsenal, Chelsea and Bayern Munich also bid to seal their place in the knock-out stages.
Mourinho led city rivals Inter Milan to the title last season and with three games left in the group stages his star-studded side, who currently have nine points and sit top of Group G, have a chance to qualify for the last 16.
Real Madrid have never won at the San Siro but will sew up qualification with a second straight win over the Rossoneri, and could do so as group leaders if Dutch side Ajax fail to win at bottom-placed French team Auxerre.
Midfielder Sami Khedira believes a solid defence will be key on the night.
"You need a good defence to win titles and if we can keep a clean sheet in Milan then we will win," said the German star.
"The great teams who have gone a long way in the Champions League have almost always been the ones who conceded the least goals. That's the key.
"Our goal in the San Siro will be to go and get all three points and move into the knockout phase."
A win would also be enough to put English giants Arsenal, Chelsea and Bayern Munich of Germany through.
Bayern, last year's runners up, travel to Romanian club CFR Cluj in Group E with a draw enough if there is a winner between FC Basel and AS Roma.
Carlo Ancelotti's Chelsea will guarantee top spot in Group F with victory over a Spartak Moscow side they swept away 2-0 at the Luzhniki Stadium two weeks ago.
Should second-placed Spartak lose, French side Marseille, in third, will hope to make the most of the situation by seeing off point-less Slovak outfit MSK Zilina.
The build-up to the Stamford Bride clash has, however, been overshadowed by ugly scenes which followed Spartak's win over rivals Zenit St Petersburg last week.
Over 100 fans were held after chairs were thrown onto the pitch and Spartak manager Valery Karpin had to be restrained after clashing with a Zenit player.
Defeat could see Spartak drop to third but they will be boosted by the fact that Chelsea's Frank Lampard will be out as he continues his recovery from hernia surgery.
Ancelotti can count on the return of defenders Jose Bosingwa and Alex, but he could opt to stick with Serb Branislav Ivanovic, who has performed well at centre-half and right-back during the pair's absence.
In Group H, Arsenal will be hoping to carry their battling Premier League form through to Europe after Alex Song's late header denied struggling West Ham a share of the spoils and kept the Gunners five points behind leaders Chelsea at the weekend.
Cameroon international Song scored in his third consecutive appearance, having also been on target against Shakhtar Donetsk and in the 3-0 win at Manchester City.
With Dutch striker Robin van Persie also on the comeback trail, Gunners boss Arsene Wenger could soon be spoilt for choice up front, as FC Shakhtar Donetsk look to avenge their 5-1 drubbing at the Emirates Stadium.
Group H tailenders FK Partizan bid for their first points at home against third-placed Sporting Braga of Portugal.