Fresh off its defeat to Chelsea, Manchester City will be keen to get back to winning terms in the league while Liverpool, the only unbeaten side left in the English top flight, hosts Jose Mourinho's Manchester United.
United has an impressive recent record against Liverpool, unbeaten in eight league games, but away fans will travel with a sense of trepidation to Anfield.
Unai Emery takes his Arsenal side, unbeaten in 21 matches in all competitions, to face struggling Southampton while Chelsea also travels to the south coast to take on Brighton and Hove Albion.
Manchester City hosts seventh-placed Everton while Tottenham Hotspur, fresh from reaching the Champions League knockout phase, faces Burnley at Wembley.
Here are some of the main talking points ahead of the weekend's fixtures in the Premier League.
Can Mourinho end Liverpool's unbeaten run?
Jose Mourinho came under fire last year for failing to attack Liverpool's then leaky defence, settling for a 0-0 draw that cost his side momentum after a fine start to the season.
Normally a draw at Anfield would be a good result but defeat on Sunday could leave United 11 points off the top four if other results go against it.
United scored four goals last week against Fulham but its attacking play has rarely been fluid this season and it is coming up against a defence that has conceded a single goal at home in the Premier League this season.
In a statistical quirk, Roberto Firmino, Mohamed Salah and Sadio Mane will all be looking for a first goal or assist in a Premier League match for Liverpool against United in more than 14 hours of football but few would bet against Salah adding to his tally in his current rich vein of form.
Jesus firing blanks
Gabriel Jesus is in a slump — he has not found the net in the Premier League since August despite chances to stake his claim in the absence of Sergio Aguero through injury.
City boss Pep Guardiola has come to the defence of the misfiring forward, saying he just needs to relax but he will be scratching his head about how to get the best out of the Brazilian.
Jesus started his City career brightly and was seen as a serious threat to Aguero's position in the team.
But the signs are that Guardiola does not trust the 21-year-old to deliver at the moment. He has started just four Premier League games this season and Guardiola left him out of the starting 11 against Chelsea last week despite the absence of Aguero.
Arsenal's defensive crisis
Arsenal is without a clutch of centre-backs for its trip to second-bottom club Southampton, seeking fresh direction under new manager Ralph Hasenhuttl.
Sokratis Papastathopoulos and Shkodran Mustafi are suspended after picking up bookings in last week's 1-0 win against Huddersfield while Konstantinos Mavropanos and Rob Holding are injured.
Club captain Laurent Koscielny could feature even though has been missing from the Premier League since May with a serious Achilles injury.
Manager Unai Emery said the club could look into recruiting a defender when the transfer window opens — both Chelsea's Gary Cahill and Eric Bailly of Manchester United have been recently linked with a move to the Emirates.
Pochettino's rising stock
Mauricio Pochettino enhanced his burgeoning reputation with an impressive 1-1 draw at Barcelona this week as his side reached the Champions League knockouts.
The downside of the success is that the Spurs boss is being linked once again to clubs higher up football's food chain, specifically Real Madrid and Manchester United.
“It's no coincidence that every day you read Real Madrid want him or United want him,” Danny Rose told the Guardian ahead of Tottenham's match against lowly Burnley.
“It's exactly what he deserves. What he has done here in the last four or five years has been amazing. He has transformed how others think of us outside the club and he has transformed how we think of ourselves and how we approach big games.”