Can Everton break their Stamford Bridge hoodoo? Will Crystal Palace end their goalscoring drought at the Etihad? Can Dimitri Payet maintain his impressive form?
The action gets underway with Champions League-chasing Tottenham hoping former striker Jermain Defoe does not score against them on his return to White Hart Lane with relegation-threatened Sunderland on Saturday.
The Saturday Night Football clash features Aston Villa against high-flying Leicester City as Remi Garde's side try to build on their first home win of the season against Crystal Palace in midweek.
Meanwhile, there are two cracking games on Super Sunday, with Liverpool looking to record just a seventh league win over Manchester United since 2004, before Stoke City aim to continue their recent good run when Arsenal visit the Britannia.
Finally on Monday Night Football, Swansea will be trying to muzzle Watford's in-form striking duo of Troy Deeney and Odion Ighalo.
With all that and more to look forward to, here's what to keep an eye out for in the Premier league...
Will Defoe come back to haunt Spurs? (Tottenham Hotspur v Sunderland, 12.45pm Saturday)
Defoe's hat-trick at Swansea on Wednesday means the Sunderland striker has now scored five times in his last two Premier League games, as many as in his previous 22 top-flight encounters.
The former Spurs striker returns to White Hart Lane on Saturday looking to net in three straight league matches for the first time since March 2008, when he was at Portsmouth.
Can Norwich record a shut-out on their travels? (Bournemouth v Norwich City, 3pm Saturday)
Norwich City travel to the Vitality Stadium to take on Bournemouth on Saturday afternoon looking to end an unwanted record.
Alex Neil's men are the only Premier League side yet to keep a clean sheet away from home this season, having let in 25 goals so far on their travels, with only Sunderland having conceded more (30).
Will Palace end their goalscoring drought at the Etihad? (Manchester City v Crystal Palace, 3pm Saturday)
Crystal Palace's goals have dried up in recent weeks, with Alan Pardew's team failing to score against Bournemouth, Swansea, Chelsea and Aston Villa in midweek.
The last time the Eagles failed to hit the back of the net in four successive league matches was in February 1998, and the odds must be in favour of that run continuing at Manchester City on Saturday; Palace have not scored in four of the last five Premier League contests with City.
Can Everton break their Stamford Bridge hoodoo? (Chelsea v Everton, 3pm Saturday)
Everton have failed to win on any of their last 20 Premier League visits to Chelsea, losing 11 of those matches.
The Toffees have also suffered late heartbreak on their previous two trips to west London, losing to goals scored in the 89th and 90th minutes.
With Everton boss Roberto Martinez's dreadful league record at the Blues' home as well - the Spaniard has tasted defeat every time he has taken a team to Stamford Bridge - few will be expecting anything other than a win for the reigning champions on Saturday.
Will Southampton continue their rise against the Baggies? (Southampton v West Bromwich Albion, 3pm Saturday)
Southampton secured a much-needed 2-0 home win against Watford on Wednesday night to help move them away from the relegation zone, with just their second victory in nine Premier League games.
Both of those wins came at St Mary's and the Saints will be eyeing up a third straight league victory at home when West Bromwich Albion travel to the South Coast on Saturday afternoon.
However, the club have not enjoyed three consecutive top-flight wins without conceding at St Mary's since last April.
Can the returning Payet keep up his impressive form at St James' Park? (Newcastle United v West Ham United, 3pm Saturday)
Payet made his first Premier League start since November 7 against Bournemouth on Tuesday after a nine-week layoff with an ankle injury.
However, the France international was quick to make up for lost time by equalising for the Hammers with a delicious free-kick midway through the second half.
The 28-year-old then created a goal on a plate for Enner Valencia as the visitors won 3-1 at the Vitality Stadium to move to within a point of the Champions League places.
And that means heading into Saturday's match at Newcastle, Payet - signed from Marseille in the summer - has now scored (six) or assisted (five) more goals for West Ham in all competitions this season than any other player.
Will Villa bring Leicester back down to earth? (Aston Villa v Leicester City, 5.30pm Saturday)
Remi Garde's first win breathed life into Villa's ailing survival bid, but they face a Leicester side on a high following a huge win at Tottenham.
Just don't expect too many goals. Villa are the lowest scorers in the division while there's been just two goals in Leicester's last four league games.
Jamie Vardy's fitness may be partly to blame - Claudio Ranieri admitted the Foxes forward hasn't trained in a month - and, just like they did against Crystal Palace, Villa's best bet could be to sit tight and wait for a mistake.
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Can Klopp end United's hold over Liverpool? (Liverpool v Manchester United, 2.05pm Sunday)
The Liverpool boss had success against Louis van Gaal in Germany, twice beating the Dutchman's Bayern Munich on the way to a Bundesliga title in 2011.
But while Klopp successfully managed to upend Bayern's traditional dominance, he faces an equally challenging task overturning Liverpool's awful recent record against Manchester United.
The Reds have just six wins over their bitter rivals since 2004, and an improving Wayne Rooney may fancy his chances after Liverpool's defensive frailties were there for all to see against Arsenal.
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Will Stoke raise their game for another big name? (Stoke City v Arsenal, 4.15pm)
They've already seen off Chelsea, Manchester United and Manchester City at the Britannia Stadium, so how will Arsenal avoid the same fate?
The Gunners don't have the best record in the Potteries, having won just once since 1991, and Mark Hughes is unbeaten in his last seven home league matches against Wenger with five different clubs.
Hughes could be without Xherdan Shaqiri, which would be a big blow for the home side, but they will fancy their chances of another big Premier League scalp.
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Can the Swans handle Deeney and Ighalo? (Swansea City v Watford, 8pm)
It's been a rough start to 2016 for Swansea, and while crashing out of the FA Cup to League Two Oxford was embarrassing, Wednesday's home loss to fellow strugglers Sunderland could prove to be the more harmful.
But the visit of Watford doesn't seem to inspire the same trepidation it might have done a month ago. Their 2-0 reverse at Southampton was their third consecutive league defeat, and the ease with which the Saints muzzled Troy Deeney and Odion Ighalo could prove the blueprint for Alan Curtis on Monday Night Football.
The in-form strikers failed to muster a shot on target between them as Southampton's 3-5-2 formation kept both in check.