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.
City overcame Stoke through an 85th-minute strike from right-back Pablo Zabaleta, whose thoughts quickly switched to the opportunity to make ground on United.
"We won the FA Cup two years ago and we want to win it again but now we will focus on Tuesday night and QPR because we want to keep winning and hopefully catch Man United," said the Argentine.
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 quarter-final against Real Madrid looming into view, thoughts are turning to a repeat of their 1998-99 Treble.
"The most important thing for me right now is to win the treble," said Mexican striker Javier Hernandez, scorer of a brace against Fulham.
"We have a chance in the FA Cup and now we have two games in the league. After that there is the international break, another league game and then Real Madrid, so we have a very good calendar and we are looking forward to it."
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.
"In the second half we showed our real level, like we did last week against Arsenal," he said.
"Oscar and Fernando scored great goals, and it was because the team were doing well and we were creating things. If we do that, Fernando, Demba (Ba), Oscar and (Juan) Mata will all score goals."
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.
Arsenal manager Arsene Wenger, whose side edged second-tier Brighton and Hove Albion 3-2 in the FA Cup on Saturday, says the fixture congestion means he has no choice but to rotate his side.
"We play against Liverpool on Wednesday, Stoke on Saturday and then the players go away for international games," he said.
"You have to rotate knowing that if it doesn't work, you will be accused of having made the wrong decision."
Aston Villa v Newcastle United, Queens Park Rangers v Manchester City, Stoke City v Wigan Athletic, Sunderland v Swansea City
Wednesday (1945GMT unless otherwise stated):
Arsenal v Liverpool, Everton v West Bromwich Albion, Norwich City v Tottenham Hotspur, Fulham v West Ham United (2000GMT), Manchester United v Southampton (2000GMT), Reading v Chelsea (2000GMT)