Arsene Wenger takes charge of Arsenal for the 1000th time with a trip to Premier League title rivals Chelsea on Saturday, while West Ham host Manchester United live on Sky Sports 1HD.
In his milestone match, Wenger will be the latest visiting manager who tries to end Jose Mourinho's long unbeaten league run at Stamford Bridge.
Contenders Liverpool and Manchester City will look to further enhance their own title credentials when they take on the two clubs at the wrong end of the table, Cardiff and Fulham respectively.
The other team currently residing in the drop zone, Sunderland, travel to face Norwich, while Crystal Palace are away to Newcastle. West Brom are also on their travels, at Hull.
Meanwhile on Saturday, Roberto Martinez's Everton can reclaim a top-five spot with victory at home to the Spaniard's former club Swansea.
After making it through to the Champions League's last eight in midweek, Manchester United will head to the East End for a Saturday Night Football encounter at West Ham.
On Super Sunday, Tottenham host Southampton before Aston Villa entertain Stoke.
Chelsea come into their showdown with capital rivals Arsenal having comfortably negotiated a route into the Champions League quarter-finals, where they will face Paris Saint-Germain. They need to get their league form back on track quickly, however, as defeat at Aston Villa last time out reduced their lead at the top of the table to just four points - and their challengers all have games in hand. Wenger is yet to get the better of Mourinho (the Portuguese has five wins and five draws from their previous meetings) and was knocked out of the Capital One Cup by the Blues boss earlier in the season. Defeat at the Bridge would be a crippling blow to the Gunners, although they were London derby winners last weekend when Tomas Rosicky's early goal sank Tottenham at White Hart Lane.
Liverpool continued their rampant form with a 3-0 victory at Manchester United last Sunday; in their 10 league fixtures in 2014, they have dropped just four points. The Reds, who are level with Arsenal in the table, now head to south Wales to take on next-to-bottom Cardiff, who went down 2-1 at Everton in their most recent excursion. Ole Gunnar Solskjaer was a deadly goalscorer in his playing days, but his side will have to be at their very best to have any chance of keeping Luis Suarez and Daniel Sturridge quiet - the strike partnership has supplied 43 top-flight goals to the Liverpool cause already this season. Suarez scored twice against Cardiff in a 3-1 win at Anfield back in December.
Due to their recent cup exploits, Manchester City are still playing catch-up in the table as they seek to rein in the teams above them and land a second title in three seasons. One eye will no doubt be on Tuesday's forthcoming derby trip across town to face United but before that, Fulham come calling at the Etihad on Saturday. Felix Magath claimed his first win in charge of the Cottagers last weekend against Newcastle, and he may try to draw inspiration from the equivalent fixture in late April 2008, when Roy Hodgson engineered a 3-2 victory away to City that paved the way for an unlikely 'Great Escape'.
Like their League Cup final conquerors City, Sunderland have either two or three games in hand on the teams around them - one of which is Norwich, who they face at Carrow Road. Wes Brown was sent off late on when the two clubs played out a stalemate on Wearside just before Christmas, and the Black Cats' last outing also finished goalless against another relegation rival, Crystal Palace. Goals are therefore likely to be at a premium in this fixture, and Chris Hughton will be desperate to nick three points having come in for further criticism from Canaries fans when his team went down 4-2 at Southampton.
Meanwhile, Palace are in the north east for the second weekend running - but Eagles boss Tony Pulis will not be able to shake hands with his managerial counterpart. Alan Pardew must serve the second game of his three-match stadium ban so his assistant John Carver takes charge of Newcastle for the afternoon. The Magpies turned in a slick performance when they brushed Palace aside 3-0 earlier in the season, but the since-departed Yohan Cabaye was the star of the show at Selhurst Park that day and United have lost four of their last six league games.
Like Magath, Pepe Mel was able to celebrate a first Premier League win since taking charge when he guided West Brom to a shock 2-1 success at Swansea last Saturday. Next for the Baggies is a trip to the KC Stadium to take on Hull and former Albion striker Shane Long, who has scored three goals in seven games since his January switch. Hull's home form has been poor since they signed off in 2013 with a 6-0 thrashing of Fulham; they have drawn one and lost four of their league fixtures at the KC since then.
Everton increasingly appear to be in a straight fight with Tottenham for a fifth-place finish and qualification for next season's Europa League play-off round. On Saturday, the Toffees host Roberto Martinez's former club Swansea at fortress Goodison Park knowing victory would move them above Spurs in the table for at least 24 hours. The Swans have only won two of their last 15 league games (only Cardiff are in worse form) and have never beaten Everton in any competition. Garry Monk has demanded a reaction from his players after their disappointing display against West Brom last weekend.
Manchester United's reward for Champions League progress was a tie with reigning European Cup holders Bayern Munich, and that quarter-final pairing has lifted the mood at Old Trafford after Sunday's humbling by Liverpool. Now David Moyes must focus minds for a Saturday Night Football encounter at West Ham, who are still fourth in the form guide despite losing their last two games. United have scored 10 goals in their previous three league trips to Upton Park, and have also looked solid at the back on their domestic travels of late. Robin van Persie will not be involved, however, after he sustained a knee injury against Olympiakos. The Netherlands striker will also miss Tuesday's derby visit of City and could be sidelined for six weeks in total.
Tottenham came close to pulling off a Europa League turnaround in Lisbon on Thursday, but eventually bowed out at the last-16 stage in a 5-3 aggregate defeat to Benfica. With Everton and United also having designs on top-six berths, Spurs' involvement in the competition next season is uncertain - and their Super Sunday visitors Southampton are by no means out of contention either. Victories over Crystal Palace and Norwich have reignited Mauricio Pochettino's hopes of a high finish, and the Argentinian's reputation continues to grow. Tim Sherwood's first game in charge of Spurs was a 3-2 triumph at St Mary's, and having been hugely encouraged by his side's performance at the Estadio da Luz, he will now be hoping to do the double over Saints.
The Super Sunday double header concludes with a mid-table meeting at Villa Park, where Aston Villa entertain Stoke. This has the potential to be a bruising battle - no Premier League club has committed more fouls than these two so far this season - and five Villa players were cautioned in the Britannia Stadium clash back in December, in which Peter Crouch scored against his old club to give Stoke a 2-1 win. However, having previously struggled on home soil this season, Villa have been applauded off by their own supporters twice already this month after beating Norwich 4-1 and Chelsea 1-0. Mark Hughes' Potters are also in good form, claiming seven points in March, and three points here would strengthen their quest for a first top-half finish.