After their 21 game winning streak was ended by city rivals Manchester United on Sunday afternoon, Pep Guardiola's men will look to bounce back against struggling Southampton.
Ralph Hasenhuttl's side have recently slipped to 14th place in the Premier League, after topping the table at one stage, and could find themselves dragged into a relegation fight if they're not careful.
Things won't get much easier for the Saints as they travel to Manchester to face the league leaders.
But how will City line-up?
Ederson has been outstanding in between the sticks this season, and is currently leading the European Golden Glove race with 15 clean sheets, and he'll start once again, looking to add to this tally.
Joao Cancelo has played at right-back and left-back almost equally this campaign, and was brought off early in the Manchester derby, suggesting he may well start against Southampton, with Kyle Walker likely to be the other full-back.
Guardiola has rotated between three centre-back options during their impressive winning run, and Aymeric Laporte was the latest to be benched, so the Frenchman could well start. Alongside him is likely to be John Stones, as Ruben Dias has started the past six outings.
Rodri has found his feet in Fernandinho's role and will start, with the now-fit Kevin De Bruyne, and goalscoring Ilkay Gundogan the most obvious midfield three.
Raheem Sterling hasn't quite hit the heights of previous seasons yet, but expect to see him from the off, and given the lack of minutes afforded to Phil Foden recently, he may well be given a chance to shine on the right hand side, with Riyad Mahrez dropped to the bench.
Despite giving away the early penalty on Sunday, Gabriel Jesus is expected to start, with Sergio Aguero's match fitness not yet up to scratch.