Paul Pogba (£7.7m) finds himself on the Manchester United bench for the first time since Gameweek 15 tonight.
The French midfielder has become a key player for Ole Gunnar Solskjaer’s men during that time and has been handed a well-earned rest for the visit of Southampton.
That could be good news for owners of Bruno Fernandes (£11.4m) or Marcus Rashford (£9.5m) though.
Pogba has often been known to limit what the Portuguese international can contribute in his number 10 role given his own propensity to take up an advanced central role and pull strings too.
Meanwhile, Solskjaer has also used him on the left-flank of attacking midfield, where Rashford produces his best game – so it will be interesting to see what impact there is tonight.
That said, Southampton are hardly in a solid state right now, especially when it comes to injuries.
Following the loan departures of Jake Vokins and Yan Valery has left them particularly short in the full-back areas.
Ryan Bertrand (£5.0m) retains his berth as the first-choice on the left of defence while Kayne Ramsay (£4.0m) fills in on the right tonight considering Kyle Walker-Peters‘ (£4.7m) most recent stand-in Ibrahima Diallo (£4.5m) is out with a muscle problem.
The combination of Oriol Romeu (£4.5m) and Diallo missing out means a first Premier League start for Alexandre Jankewitz (£4.5m) in central midfield alongside James Ward-Prowse (£6.0m).
Ralph Hasenhüttl can call on his first-choice forwards though with Danny Ings (£8.4m) and Che Adams (£5.9m) both up-front while new loan signing Takumi Minamino (£6.0m) is not involved yet.
Newcastle are forced into just the one change for their Gameweek 22 meeting with Crystal Palace.
Jamaal Lascelles (£4.2m) sustained a muscle injury in the recent 2-0 win at Everton, which sees Ciaran Clark (£4.5m) come back into the side.
Ryan Fraser (£5.6m) and Miguel Almirón (£5.6m) provide the width in a 4-5-1 formation aimed at Callum Wilson (£6.7m) while Allan Saint-Maximin (£5.1m) lies in waiting on the bench.
For the second match in a row, Crystal Palace are in 4-2-3-1, an interesting development considering how long Roy Hodgson has favoured 4-4-2.
Patrick van Aanholt (£5.4m) earns back-to-back starts at the expense of Tyrick Mitchell (£3.9m) for the first time since Gameweek 15, suggesting the Eagles’ manager prefers the Dutch international when playing 4-2-3-1.
Wilfried Zaha (£7.2m) is back in the attacking midfield trio again, joined there by Eberechi Eze (£5.8m) and Jordan Ayew (£5.6m) in support of Michy Batshuayi (£5.7m).
And joining Mitchell on the bench is Jean-Philippe Mateta (£6.0m) still waiting for his first Premier League start.
Gameweek 22 Starting Line-ups
Manchester United XI (4-2-3-1): De Gea; Shaw, Maguire, Lindelöf, Wan-Bissaka; McTominay, Fred; Rashford, B Fernandes, Greenwood; Cavani.
Southampton XI (4-4-2): A McCarthy; Bertrand, J Stephens, Bednarek, Ramsay; Djenepo, Jankewitz, Ward-Prowse, Armstrong; Adams, Ings.
Newcastle United XI (4-5-1): Darlow; Lewis, Clark, Schär, Manquillo; Fraser, Hendrick, Shelvey, Hayden, Almirón; Wilson.
Crystal Palace XI (4-2-3-1): Guaita; van Aanholt, Dann, Cahill, Clyne; Milivojevic, Riedewald; Zaha, Eze, Ayew; Batshuayi.