Milan edged their way though group H alongside Barcelona, while Atletico thoroughly dominated in group G, taking 16 out of 18 possible points.
While not a traditional powerhouse, Atletico has broken through on the world stage in a big way this year, as they are currently joint-top of the table in La Liga with Barcelona and Real Madrid. Indeed, they have taken four out of six points against those two sides so far in the league, indicating Simeone has instilled a fearless attitude in his side.
Milan's issues have been well-chronicled, with financial issues forcing the sale of many of the club's top players over the past several years. The retirement and departures of club legends have also contributed to the team's downfall in the past two seasons.
However, Milan impressively qualified for the Champions League on the final match day in Serie A last season, and they have once again made it into the knockout stages, highlighting a tendency for the side to step up in European competition.
As Clarence Seedorf prepares his side for what is sure to be an enterprising attacking side on Wednesday, several of his players must stand out for Milan to have a chance at progressing.
Mario Balotelli has endured a somewhat shaky season, unsurprisingly being in the news on several occasions and missing time due to suspension and injury.
However, he has demonstrated a more mature approach in recent weeks, and Milan must be hoping he continues to improve his form heading into this match.
Balotelli is the one player Milan have who is capable of swinging a match of this magnitude single-handedly. One need look no further than his wonder goal on Friday against Bologna for proof of this.
With Stephan El Shaarawy out, Balotelli is the undisputed focal point of the attack, and he simply must deliver for Milan to have any chance of getting a result.
One of former manager Massimiliano Allegri's main criticisms was his tendency to rely on the individual brilliance of his stars, first Zlatan Ibrahimovic, then El Shaarawy and Balotelli last season.
From a tactical viewpoint, Seedorf surely will not develop a game plan based around hoping for a moment of magic from Balotelli, yet he is the player who is most capable of rising to the occasion.
Balotelli's performance Wednesday night will go a long way in determining the likelihood of Milan advancing to the second leg in Madrid with an advantage.
Adil Rami has been a pleasant surprise for Milan, quickly becoming a stalwart in defense after his January arrival from Valencia.
Rami helmed a very good back line in Valencia for several years, going into the knockout stages of the Champions League a couple of times. As such, he has invaluable experience at this level.
While he has more familiarity with Atletico Madrid than most Milan players do due to his time in Spain, Rami's key attribute is his positioning and tackling ability, and these things will serve Milan best when they are dealing with the threat of Diego Costa and possibly David Villa up front.
Rami can be relied upon to make a positive impression in the match, but the more pertinent question is whether he can cover up the deficiencies of his partner in the center of defense. In all likelihood, this will be Philippe Mexes, whom Rami has experience with on the French national team.
Milan fans will be hoping neither Daniele Bonera nor Cristian Zaccardo partner Rami, as their frequent individual errors could cost Milan dearly against a side the quality of Atletico Madrid.
Rami cannot do it all on his own, but his presence undoubtedly makes Milan's defensive line far more stable than it was entering 2014.
The former Atletico Madrid goalkeeper faces his former team, and is an absolutely essential part of Milan's side heading into the match.
It can reasonably be assumed that Atletico, while possessors of a different style of play, will most resemble Barcelona in terms of the teams Milan has faced in the Champions League.
As such, they will bring a fierce attacking drive to the San Siro, and given the state of Milan's midfield will be in possession of the ball the majority of the time.
A hallmark of Milan's matches with Barcelona over the past couple years has been the relative onslaught of shots on Milan's goal—indeed, even the matches against Ajax saw Milan face a flurry of shots.
It is imperative Abbiati be on top of his game and not make any mistakes because it can reasonably be assumed Atletico's clinical finishers will pounce.
Abbiati is not a world-class goalkeeper, yet he has produced some fine performances over the years in the Champions League.
He must produce a flawless performance to ensure Milan get a positive result on Wednesday night.