Manchester City travel to Aston Villa on Saturday desperately seeking to halt their dramatic slide while Chelsea have the chance to go top of the Premier League, if only briefly.
Current leaders Liverpool face a tricky trip to Tottenham after a wobble while Manchester United are seeking to win two Premier League games in a row for the first time this season.
AFP Sport picks out some of the major talking points ahead of the weekend action.
Manchester City lost 1-0 away to Aston Villa last December but that proved to be their final defeat of the season as they romped to a fourth straight Premier League title.
That loss for Pep Guardiola's men came after three straight draws — which was then a slump by City's sky-high standards.
This time they travel to Birmingham in a deep rut, with eight defeats from their past 11 matches in all competitions.
City's chances of winning a fifth straight English top-flight title appear to be over but they must somehow halt their astonishing slide.
Guardiola took the blame after last week's painful 2-1 derby defeat to Manchester United, saying he was not "good enough", though Phil Foden said the players still believed in their boss.
Fifth-placed City, nine points behind Liverpool having played a game more, have lost five of their past seven Premier League games, as many as they had in their previous 67 matches combined.
Seventh-placed Villa have been inconsistent but injury-hit City have lost the habit of winning — suffering an apparent collective crisis of confidence.
Arne Slot has made replacing Jurgen Klopp as Liverpool manager look easy. But is he about to face his first major challenge?
Earlier this month, the Reds were nine points clear at the top of the Premier League and seemingly on course for a record-equalling 20th English top-flight title.
But they could kick off at Tottenham on Sunday behind Chelsea, who are seeking a sixth straight league win at struggling Everton earlier in the day.
Liverpool have drawn their past two league matches, against Newcastle and Fulham, but beat Southampton in the League Cup quarter-finals this week to stay on track for a first trophy of Slot's reign.
They are still firm favourites to win the league but Chelsea are gathering momentum under new manager Enzo Maresca.
It is difficult to predict which Tottenham team will turn up on Sunday after seven wins and seven defeats in their 16 league games so far.
But one thing is for sure — Ange Postecoglou's team will not sit back — only Chelsea have scored more than their tally of 36 league goals this season.
Leicester and Wolves have both sacked their managers this season, spooked by poor starts to the Premier League campaign.
The two sides meet at the King Power on Sunday in a must-win match for the visitors, who this week appointed Vitor Pereira as their new coach following the dismissal of Gary O'Neil.
Wolves are second from bottom of the Premier League after four straight defeats, with a paltry nine points from 16 games — five points behind Leicester, who are just outside the relegation zone.
Chairman Jeff Shi thanked Pereira, a league winner in Portugal and Greece, for taking on the tough challenge at Molineux.
The reality is that the Midlands club are already running out of time.
After the Leicester match, Wolves head into a daunting run of fixtures against Manchester United, Tottenham and high-flying Nottingham Forest.
Ruud van Nistelrooy started off brightly at Leicester, winning his first match and drawing the second but the Foxes suffered a demoralising 4-0 defeat at Newcastle last week and if results go against them they could end the weekend in the drop zone.
