Liverpool face a derby clash against Everton as they lick their Champions League wounds while Tottenham travel to Arsenal with a spring in their step on a weekend of big-city derbies.
Jurgen Klopp's team lost 2-1 to Paris Saint-Germain in midweek, meaning their bid to reach the knockout stages in Europe will go to the last game against Napoli, while Spurs face the daunting task of beating Barcelona to progress.
But both clubs will have to put their continental ambitions to one side as they attempt to stay on the coat-tails of Pep Guardiola's Manchester City in the Premier League.
Chelsea take on Fulham and one of their former managers in another London derby but Claudio Ranieri's side will travel the short distance to Stamford Bridge with new-found confidence after arresting a run of six Premier League defeats.
Jose Mourinho's misfiring Manchester United play Southampton away after edging past Swiss side Young Boys into the Champions League knockout phase. AFP Sports picks out some of the main talking points ahead of the weekend fixtures in the Premier League.
'Perfect' time to play Arsenal
Third-placed Spurs head to the Emirates stadium buoyed by last week's 3-1 victory against Chelsea and their 1-0 win against Inter Milan in midweek, which keeps alive their hopes of reaching the Champions League knockouts.
Midfielder Harry Winks, who came agonisingly close to scoring against Inter at Wembley when he hit the bar from distance, said it was the "perfect" time to play Arsenal after six straight wins in all competitions.
"It is going to be another difficult game, so we have to get right and physically prepared for it, because it is going to be another battle," said the England international.
"It is a game the fans want to win and one that we want to win. Three games in a week is going to be tough, but confidence is high." Everton derby pain
Everton have a shocking record against city rivals Liverpool, not tasting victory in the derby since 2010 and failing to win at Anfield since 1999.
Marco Silva's task looks daunting on Sunday but Everton travel in hope after a solid start to the season that sees them in sixth, 11 points behind Klopp's team.
Liverpool, second in the table, come into the match smarting after their disappointing defeat in Paris and Klopp is expecting a tougher test from Everton than in previous seasons.
"This game is isolated from the season," he said. "It's a derby, it's at home. Everton are doing really well this season, they're a completely different cup of tea, I would say, to the last few years so it will be a tough one." Time running out for misfiring United
Jose Mourinho appears to be flailing around for answers to his side's lack of fluency but getting nowhere despite a changing cast of characters.
He demoted Paul Pogba and Romelu Lukaku to the substitutes' bench for the match against Young Boys and Alexis Sanchez was missing from the squad entirely but United still failed to find any rhythm.
United are already seven points adrift of fourth-placed Chelsea and show no sign of putting together a run to haul themselves into contention to qualify next season's Champions League.
Midfielder Marouane Fellaini, who scored the late winner against Young Boys, said the mood in the camp was upbeat following the 1-0 win, despite United's patchy form this season.
"Criticism is part of football but we have to work," he said. "We are a team, we are together, and give everything too. Together we have to move forward and take the points.