If the Citizens want to advance to the knockout stages of the UEFA Champions League, whom should the Italian tactician place his trust in to win this battle?
Read on to find a predicted starting XI for City in a 4-2-3-1 formation.
There's no question who's starting in goal against the most prestigious visitors the Etihad Stadium has ever hosted.
Hart could have conceded seven goals to Aston Villa at the weekend and still walk into this side as the shot-stopper—Costel Pantilimon knows his role is a peripheral one.
This is shaping up to be one of the most difficult the England international will ever play as his ailing defence face up to Cristiano Ronaldo and co.
Vincent Kompany and Matija Nastasic
Despite his abject form this season, Roberto Mancini will continue to field captain Kompany until he finds his feet and rightly so.
It should be noted, however, that if ever there was a game that the Belgian needs to rediscover last season's form, this is it.
A near-spectacular own goal against against Aston Villa could have taken the gloss off a 5-0 drubbing this weekend, but as it happens the City defence go into this game on the back of a clean sheet.
Nastasic partnered Kompany in a quiet weekend, while he was also fielded at the Santiago Bernabeu last month. With Joleon Lescott still not managing to earn Mancini's trust, it's hard to see him starting on Wednesday.
Maicon and Gael Clichy
After this weekend's performance, Maicon's name may well be the first on the team sheet.
He's been hampered by injuries early on during his Manchester City career, but he finally exploded into life against Aston Villa.
Yes, he was facing a rookie left-back in Enda Stevens but you can only beat what's in front of you, and Maicon absolutely destroyed the Irishman.
The left-back spot, on the other hand, is completely up for grabs. Aleksandar Kolarov has been used as an impact substitute lately and in actual fact plays left midfield at times.
Clichy has been looking impressive recently, and the Frenchman deserves a start here.
Javi Garcia and Yaya Toure
Roberto Mancini should go with a 4-2-3-1 initially, so expect to see Toure take up his customary deep role alongside one of Garcia or Gareth Barry.
The Manchester City manager has tended to lean toward Garcia in European battles as he is slightly more mobile than Barry is, and this holding duo will be vitally important in feeding the ball to the Citizens' danger men.
David Silva, Sergio Aguero and Samir Nasri
During City's 5-0 victory over Aston Villa, these three ran riot as an advanced midfield line behind Carlos Tevez.
Their interchanging of positions, fluid movement and slick passing was simply too much for Ron Vlaar and co., and in truth there aren't any defensive lines in the world who can live comfortably with this attacking potency.
City's hopes of winning rest on the shoulders of these three.
We should see the in-form Argentinian striker Tevez lead the line at the Etihad Stadium on Wednesday, although his duties and responsibilities will be fluid as ever.
Expect him to drop deep or drift wide to find space and frequently interchange with his advanced midfield three, making him difficult to mark and even more difficult to foil.
Tevez's movement could be the determining factor in the game, as he will need to provide enough chaos to unsettle Real Madrid's stellar holding midfield pivot.
As suggested in my early preview of the game, Edin Dzeko could be a key factor coming off the bench.
The Bosnia and Herzegovina international doesn't want to be known as a super sub, insisting you can call him anything else (via The Telegraph). Assistant coach David Platt has echoed that sentiment (via The Sun).
Unfortunately for the target man, he's a proven impact player with five goals off the bench in critical situations such as West Brom away, Real Madrid away and Fulham away.
The quick interplay between David Silva, Samir Nasri, Carlos Tevez and Sergio Aguero is a starting point, but if it doesn't go to plan, Roberto Mancini needs to make sure he's got this man ready to come off the bench.