Felix Magath begins his quest to guide rock-bottom Fulham to safety on the road at West Bromwich Albion, while leaders Chelsea welcome Everton to Stamford Bridge.
Arsenal and Manchester City will be hoping to enjoy home comforts and keep their title chases on track, against Sunderland and Stoke City respectively, before Liverpool play host to Swansea City on Sunday.
Manchester United will want to close in on the European places when they take in a trip to Crystal Palace, live on Sky Sports, while Cardiff City will aim to climb out of the drop zone at home to Hull City and West Ham United will endeavour to keep their recent revival going against Southampton.
The Sky Sports cameras will then be in the North East and East Anglia for a Super Sunday double-header that opens with Newcastle United entertaining Aston Villa and closes with Tottenham Hotspur's trip to Norwich City.
Table-topping Chelsea get the weekend action up and running on Saturday lunchtime as they welcome Everton to west London. The Blues are unbeaten in their last 11 Premier League fixtures, and have moved one point clear at the summit as a result. They are now there to be shot at, and Everton will want to be the ones to knock them from their lofty perch. The Toffees have failed to emerge victorious in their last 18 visits to Stamford Bridge, but did overcome Jose Mourinho's men 1-0 in the reverse fixture back in September, so know what it takes to get the job done.
Second-placed Arsenal will know by the time they take to the field against Sunderland whether there is any chance of them ending the day back in first place, and will be desperate to ensure that they offer a positive response to their European setback against Bayern Munich in midweek. The Gunners have now won just one of their last four games in all competitions - an FA Cup clash with Liverpool - and know they need to rediscover their spark if they are to remain in contention for the top-flight crown. Sunderland are more concerned with events at the opposite end of the division, with Gus Poyet's cup specialists having slipped back into the relegation zone.
Manchester City are also in action at three o'clock on Saturday, and have a continental itch of their own to scratch upon their return to domestic duty. They need to get a disappointing defeat to Barcelona out of their system as quickly as possible and get back to the business of blowing opponents away at the Etihad Stadium. Stoke City are unlikely to be relishing a trip to the North West, having been beaten in each of their last five visits - conceding 14 times and offering no reply. Mark Hughes may feel that he still has a point to prove on his former stomping ground, though, and masterminded a goalless draw with City at the Britannia Stadium earlier in the campaign.
Elsewhere, West Ham will be looking to make it four wins in a row when Southampton arrive at Upton Park. The Hammers, who found themselves languishing inside the bottom three a few weeks ago, are now 11th, with only goal difference keeping them out of the top half. Another positive result this weekend would fire them into the top 10 and put further daylight between them and the top-flight trapdoor. Saints have, however, become a tough nut to crack again, with Mauricio Pochettino's side unbeaten in the league since New Year's Day - a run of six fixtures.
Fulham can only dream of such a run at present, and have made their second managerial change of the season in an effort to bring about a reversal in fortune. No-nonsense former Bayern Munich boss Magath has been drafted into their hot-seat, becoming the first German coach to take charge of a Premier League side in the process. He inherits a team that has gone six games without a win, losing five of those contests to be cast four points adrift of safety. West Brom will want to stick the knife in a little deeper on Saturday, with the Baggies - who are perched just outside the drop zone - still looking for a first win of their own under new boss Pepe Mel.
Should the Baggies come unstuck at Craven Cottage, the door will be opened for the likes of Cardiff to climb the standings. The Bluebirds are second from bottom right now, with the arrival of Ole Gunnar Solskjaer yet to have the desired impact. Goals have been in short supply for the Welsh outfit - with only Crystal Palace finding the target on fewer occasions this term - while defensive leaks are also proving costly - with only Fulham having conceded more. Hull will be hoping those factors work in their favour, with Steve Bruce's side looking anxiously over their shoulder again at the basement battle unfolding below them.
The final game on Saturday will be screened live on Sky Sports, with Crystal Palace hoping to become the latest side to make their own piece of history against Manchester United. The Eagles have never beaten the Red Devils in Premier League competition, but know the reigning champions have endured their fair share of struggles this season. Three wins in four suggest that Palace should enter the contest full of confidence, with Tony Pulis having helped to turn their fortunes around. David Moyes is still looking to do that at Old Trafford, with no win in three all but ending any hope United had of staging a late surge for a top-four finish.
Liverpool are the holders of the final UEFA Champions League spot at present, but are setting their sights much higher than that. The Reds have been able to maintain their form impressively this season, keeping them within four points of the leaders. They will be the last of the title hopefuls in action in the latest round of fixtures, and that could play into their hands. As could the recent turmoil at Swansea, with Garry Monk still finding his managerial feet after being asked to fill the shoes vacated by the ousted Michael Laudrup. He has started well, picking up four points from two outings, but will be aware that a trip to Anfield provides him with his sternest test yet.
Also in action on Sunday lunchtime will be Newcastle and Aston Villa. The Sky Sports cameras will be at St James' Park to see if Alan Pardew can start to ease some of the pressure on his shoulders, with the Magpies in the middle of an alarming slump. Three successive defeats, and no win in four, have halted the Toon Army emphatically in their tracks. The one crumb of comfort for Pardew and his troops is that Villa have fared little better of late, while the Midlanders also tend to struggle on Tyneside - failing to take maximum points from any of their last seven journeys north.
Following the final whistle at Newcastle, attention will then switch to events at Carrow Road as Norwich prepare to take on Tottenham. The Canaries are another of those sides struggling for consistency, and find themselves in trouble as a result. It is possible that they could end the weekend inside the bottom three, and that is unlikely to do Chris Hughton's claims to a long-term role in Norfolk any good - with Norwich admitting in the week that they have contingency plans in place should they need to mix things up in the dugout. Spurs have already done that this season and will be pleased with how rookie boss Tim Sherwood has fared. A top-four finish is still up for grabs, while a feel-good factor has been returned to the ranks at White Hart Lane.