It's a match which could truly turn the tide for Milan if the result goes their way, but they'll face a stiff test at the Camp Nou against a rabid Barcelona side that's even deeper than they were last season.
With their Serie A campaign all but lost, the Rossoneri must put all their bags in the European basket and give their fans some form of optimism, after the last few weeks have seen turmoil engulf the storied franchise.
The much-maligned Massimiliano Allegri now has the unenviable task of steering the crooked ship back on course, as he tries to do his best with an injury-depleted Milan side that only has 18 available bodies for Wednesday's fixture.
Christian Abbiati is expected to make his return between the pipes, as Marco Amelia is now suffering from an injury woe of his own. Abbiati has been shaky this season, and it's expected that the young Brazilian Gabriel will continue to be Milan's starter in Serie A, as he wasn't called up for the initial Champions League squad.
Daniele Bonera will return to the squad and could make his appearance for the first time this season in a decimated back line that's desperately looking for bodies. Bonera was injured on July 27 of this year and would be horribly rusty if relied upon from the first minute.
Philippe Mexes is the only guarantee at the back, with Ignazio Abate and Kevin Constant as the two choices for both full-back positions.
In the midfield, Milan will be without Antonio Nocerino, if that even matters. Nigel De Jong is expected to take on the defensive midfield position, with Riccardo Montolivo offering a bit of guile, and either Sulley Muntari or Andrea Poli taking the third spot in the center of the park.
The three midfielders have the gargantuan task of trying to quell the famous Barcelona "tiki-taka" style of possession play, which wears down opponents and frustrates them rapidly.
Montolivo will be tasked with leading the occasional counterattack and providing a quick ball up front, as Barcelona loves to pressure opponents high up the field, forcing them to make quick, sloppy reactions.
In Milan's 4-3-3, it'll be interesting to see who will make up the attacking trident. The obvious choices are Mario Balotelli and Kaka. Super Mario is living the worst period of his Milan career, as he has failed to hit the back of the net regularly and has irked Milan supporters with idiotic fouls which have led to a plethora of suspensions.
According to a Champions League preview in Italian newspaper La Gazzetta dello Sport, the right-wing position will be occupied by Valter Birsa instead of Robinho. The Slovenian lacks the pure technique of the Brazilian but runs hard and tracks back, two characteristics that Allegri loves from his wingers.
It's unfortunate that we won't see Robinho and Kaka from the first minute, as their chemistry together really showed in the first match against Barcelona this season, and it was their brilliant link-up play which led to the first goal.
In the end, expect a frenzied performance for the Blaugrana, as they will most likely choke Milan in their own half for most of the match. Milan must be clinical with the few chances they will get, and Barcelona's defense certainly isn't watertight.