How will Virgil van Dijk be received on his return to Southampton? Will Man City overcome their bogey visitors? We take a look at the big questions ahead of the weekend.
Manchester City kick things off on Sky Sports Premier League at 5.30pm on Saturday against Leicester, while Super Sunday sees Newcastle host Manchester United and Liverpool travel to Southampton.
Chelsea and West Brom round it all off on Monday Night Football at Stamford Bridge, with kick-off at 8pm.
Meanwhile, Tottenham play north London rivals Arsenal at Wembley.
Manchester City v Leicester: Will City overcome their bogey visitors? (Saturday from 5.15pm, Sky Sports Premier League)
Pep Guardiola's men will have to be on their guard with the Foxes in town, even without Riyad Mahrez, who continues to be absent from the first-team after City's deadline day bid for him was rejected.
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City have lost 67 per cent of their home Premier League matches against Leicester - their highest percentage of home defeats against any club in the Premier League.
Newcastle v Manchester United: Can Newcastle record their second league win of 2018? (Super Sunday from 1.30pm on Sky Sports Premier League)
Rafa Benitez's men are winless in eight Premier League home games (D3 L5), which is bordering on becoming their worst ever run in the competition. They last went nine games without a win at St James' Park in August 1999.
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Interestingly, Jose Mourinho has never won a Premier League match at St. James' Park in six attempts and has managed more away league games at Newcastle without winning than at any other club in his managerial career.
Southampton v Liverpool: How will Virgil van Dijk be received on his Southampton return? (Super Sunday from 4.15pm on Sky Sports Premier League)
Virgil van Dijk has admitted he has prepared himself for a raucous welcome from the Saints fans. The Dutchman became the world's most expensive defender in January after the Reds paid a fee in the region of £75m for his services after a prolonged transfer saga that involved him handing him a transfer request.
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Saints ended their 12-game winless run with victory at West Brom last week, and are looking to secure back-to-back wins in the Premier League for the first time since April 2017.
Chelsea v West Brom: Is it time up for Antonio Conte? (Monday Night Football from 7pm on Sky Sports Premier League)
Chelsea are set to stick with head coach Antonio Conte until the end of the season, according to Sky sources, despite a clear downturn in results, which included a 4-1 defeat at Watford on Monday Night Football. However, surely another defeat against a team bottom of the league would give the Chelsea board a serious decision to make.
However, the Blues have won all three Premier League meetings against West Brom under Conte without conceding a single goal.
Tottenham v Arsenal: Will Spurs get their revenge in the north London Derby? (Saturday, 12.30pm)
Tottenham have lost just once in their last seven Premier League appearances against Arsenal which came earlier this season in a 2-0 loss at the Emirates Stadium.
Mauricio Pochettino's side will inevitably be looking to win not just for bragging rights, but to distance themselves further from Arsenal in the table while potentially leapfrogging Chelsea into fourth depending on how Antonio Conte's side fare against West Brom on Monday Night Football.
Everton v Crystal Palace: Will Allardyce's former club finally beat Everton? (Saturday, 3pm)
Sam Allardyce faces the club he last left in Crystal Palace on Saturday as his Everton side look to bounce back from the 5-1 thrashing by Arsenal last weekend. Everton are unbeaten in each of their last six Premier League matches against Palace so should enter the game full of confidence.
However, Everton have won just once in the Premier League since December 18, so will have to play at their best if they wish to overcome a Palace side keen to record a win after consecutive 1-1 draws against West Ham and Newcastle.
Stoke v Brighton: Will Paul Lambert get Stoke out of the danger zone? (Saturday, 3pm)
Lambert is looking for his second win as Stoke boss and will try and do so against Brighton, who have not scored a single goal in any of their last four visits to the bet365 Stadium.
But the visitors have an in-form goal-scorer in Glenn Murray, who has netted in five of his last seven games in all competitions.
Containing Murray's threat and grabbing a victory could see Stoke out of the relegation zone by the end of the weekend.
Swansea v Burnley: Will Burnley end their winless Wales hoodoo? (Saturday, 3pm)
Burnley haven't won any of their 15 away matches in Wales since beating Cardiff back in April 2000, so they will be looking to put that record to bed on Saturday.
However, Swansea have enjoyed a resurgence under Carlos Carvalhal while Burnley are without a Premier League win in nine games. Victory for Burnley, though, could move them closer to the top six places should Arsenal slip up against Spurs earlier in the day.
West Ham v Watford: Will Watford build on their historic Chelsea victory? (Saturday, 3pm)
Watford are looking to win back-to-back league games for the first time since November, following their 4-1 victory against Chelsea on Monday. Once again, the decision to change a manager mid-season has yielded an upturn in results with Javi Gracia taking four points from his first two games in charge.
David Moyes faced Javi Gracia twice when he managed Real Sociedad in La Liga - he drew one and lost one against Gracia, who was then in charge of Malaga.
Huddersfield v Bournemouth: Will the hosts end their eight-game winless run in the Premier League? (Sunday, 12pm)
David Wagner's side are starting a Premier League match in the relegation zone for the first time, having dropped into the bottom three following last week's defeat to Manchester United.
Their slide down the league has resulted in them going odds-on to go down in the relegation betting markets and Wagner has a job on his hands to arrest the slide.
Bournemouth won the reverse fixture 4-0 at the Vitality Stadium earlier this season, despite having Simon Francis sent off in the first half.