Ignominious Champions League exits for both Manchester giants have made weekend Premier League victories essential for United and City as re-invigorated Chelsea hope to join the party at the top of England's top division.
Premier League champions United hope a resounding victory on Saturday (1500) over lowly-placed Wolverhampton at Old Trafford will provide the perfect tonic for their mid-week hangover.
The bitter disappointment of getting knocked out at the Champions League group stage by Basel has been compounded by an injury to defensive rock and club captain Nemanja Vidic.
The Serbian was stretchered off with what appeared a serious injury and he is unlikely to feature against Wolves, a team lying 16th in the Premier league and fighting a fierce relegation battle.
But unlike their arch-rivals across town, Manchester City players will not be afforded a seemingly easy return to domestic competition as they face Chelsea, a team bristling with confidence after their 3-0 win over Valencia and convincing progression to the last 16 of the Champions League.
The Monday night clash between England's wealthiest clubs will also be seen as a make-or-break game for Chelsea as it offers Roman Abramovich's team a chance to rescue their Premier League season.
After blasting through to the last 16 of the Champions league as group leaders, the West Londoners take on unbeaten City with plenty of ground to make up.
Chelsea are 10 points adrift and have been beaten this season by champions Manchester United, Arsenal and Liverpool.
Manager Andre Villas-Boas held up the clash at Stamford Bridge as a potentially defining moment of the season that could re-ignite Chelsea's domestic title challenge and playmaker Juan Mata agreed.
It is not impossible, said the Spanish World Cup winner. There are so many weeks until the Premier League finishes. We will keep going every week to win and to be closest to the leader.
They are the leaders, they win in every game and we hope that here at Stamford Bridge they will have a difficult game, added Mata.
We lost against Liverpool, against Arsenal, against Manchester United, but we hope that against Manchester City we'll change this.
Frank Lampard will be in contention for a place in the starting line-up, after being left out of the team that beat Valencia 3-0 in the Champions League on Tuesday night, and with a point to make.
He has been in a fantastic moment and is sure to threaten for the starting 11 on Monday, said Villas-Boas, who complained after the Valencia game that City were given a far easier ride by the media over their European difficulties.
Arsenal, who host Everton on Saturday (1500) will be watching the Chelsea v Manchester City game in the hope that a victory for the fourth-placed Londoners will make the competition for the Premier League title a five-horse race.
(Reporting by Alan Baldwin, editing by Ed Osmond)