Having trailed Premier League leaders Manchester United by seven points as recently as January 18, Manchester City can cut the gap to just two points with victory at Queens Park Rangers on Tuesday.
United would be able to restore their advantage by beating Southampton on Wednesday, but City's trip to the league's bottom club gives them an opportunity to inject tension into a title race that had looked set to become a procession.
City won 1-0 at Stoke City on Saturday to reach the fifth round of the FA Cup, but victory came at a cost as captain Vincent Kompany was forced off in the first half with a calf injury.
The English champions have ruled Kompany out of the trip to QPR, leaving manager Roberto Mancini with Matija Nastasic and Joleon Lescott as his only available senior centre-backs.
QPR's season met with further embarrassment on Saturday when they lost 4-2 at home to Milton Keynes Dons of third-tier League One to go out of the FA Cup.
The London club are five points adrift of safety with 15 games remaining and manager Harry Redknapp will recall his most important players for City's visit after making nine changes against MK Dons.
United will watch Tuesday's encounter at Loftus Road with interest, as they embark upon a period of matches that could define their season.
Alex Ferguson's men swept past Fulham 4-1 in the FA Cup on Saturday and with a Champions League quarterfinal against Real Madrid looming into view, thoughts are turning to a repeat of their 1998-99 Treble.
Third-place Chelsea will hope to put two damaging cup results behind them when they visit improving Reading on Wednesday.
The European champions went out of the League Cup after drawing 0-0 at Swansea City on Wednesday, before a late Fernando Torres equaliser was required to snatch a 2-2 draw at third-tier Brentford in the FA Cup on Sunday.
The setbacks have only served to increase the unpopularity of interim Blues coach Rafael Benitez, but he said his side's second-half reaction at Griffin Park augured well.
Another team smarting from an FA Cup embarrassment are Liverpool, who belied a recent upturn in their league form by losing 3-2 at third-tier Oldham Athletic in the fourth round on Sunday.
On Wednesday they travel to Arsenal, one position above them in the table in sixth place, with both sides desperate to close the gap that separates them from the Champions League places.