Aymeric Laporte has undergone surgery on his right knee following an injury picked up against Brighton & Hove Albion at the weekend.
The French defender went off on a stretcher in the first-half, leaving the Blues light at the back.
In the summer Pep Guardiola admitted that the club were chasing a centre-back, including Harry Maguire, although were unable to pull off the right deal for the right price, potentially proving costly now following Laporte's injury.
City haven't commented on how long Laporte will be out for, although reports suggest he may be out for the remainder of the year.
Here are some possible replacements for Laporte to partner Nicolas Otamendi at centre-back.
Firstly, and perhaps the most obvious suggestion would be John Stones. The English defender has recently had injury problems of his own, although should return soon - a relief for Guardiola.
City's number five has featured 42 times for City in the last two Premier League seasons, picking up two titles and gradually becoming one of the more experienced players amongst City's squad.
If he can recover in time for the return of the Premier League following the international break, Stones seems the most likely to partner Otamendi in Laporte's absence.
Fernandinho has become a veteran amongst the city squad, playing a crucial role in their recent success, anchoring the midfield and protecting the Citizens' backline.
With the arrival of Rodri from Atletico Madrid in the summer, the Brazilian has been pushed out of his favoured position, although has indicated that he could feature more regularly this season as a central defender.
Following Laporte's injury, Fernandinho was asked whether he was ready to step into centre-back, he said, "I've been training in this position the last couple of weeks," before adding. "We still have two centre-backs but I can play in this position."
Another player that isn't naturally a centre-back, although could step into Laporte's shoes is Kyle Walker.
The English right-back played in the centre-back role for his nation in last years FIFA World Cup, meaning the position isn't completely foreign to him.
The Champions this summer brought in Joao Cancelo from Juventus, who is also a right-back, but has had limited playtime thus far due to Walker being City's first choice.
Should Guardiola opt to slot Walker in at centre-back, it would enable Cancelo to feature in the side in his favoured right-back position, allowing the former Juve man to show his new boss what he's capable of, as well as gain valuable experience in the Premier League.
Despite only having two fit centre-backs, and the fixtures piling on in Europe as well as the Carabao Cup, it may not be as bad as it seems for Guardiola and City due to the versatility of many players in their squad.