Marcus Rashford and Bukayo Saka have been ruled out of England's World Cup qualifiers against Albania and Poland.
The Three Lions got the road to Qatar off to a straightforward start against San Marino on Thursday, with Dominic Calvert-Lewin scoring a brace in a comprehensive 5-0 Wembley win.
Rashford and Saka both missed that match and the Football Association has confirmed the pair will be absent for the entirety of this month's World Cup qualification triple-header.
England travel to Tirana on Sunday and welcome Poland to Wembley on Wednesday – the final matches before Gareth Southgate names his squad for this summer's rearranged European Championships.
"Marcus Rashford and Bukayo Saka will play no part in England's forthcoming 2022 FIFA World Cup qualifiers," the FA said in a statement.
"Rashford reported to St. George's Park with an injury that ruled him out of the 5-0 win against San Marino and, following further assessment, it has been decided he will continue his rehabilitation with Manchester United.
"Saka had remained at Arsenal for further assessment on an ongoing issue with the hope of joining up with the Three Lions but will now not be available for the fixtures against Albania and Poland."
Arsenal teenager Saka was one of the highlights of a challenging autumn international schedule, making his debut against Wales in October and going on to win a further three caps.
Rashford only appeared in two of England's eight fixtures in 2020 and has now officially been ruled out of with a foot injury that made him miss Manchester United's FA Cup quarter-final defeat at Leicester.
"Well, they're both doubtful (for this triple-header)," England boss Southgate said on Wednesday. "I'd say Marcus is more doubtful than Bukayo at the moment but we're going to assess them.
"Marcus has been very keen to be with us. He obviously wasn't with us so much in the autumn so I think he's been keen to be part of the group and get with us.
"Bukayo has needed to have some sort of investigations at the club first so hasn't been able to join us yet, but hopefully he will be in the next couple of days."
While Rashford has been unable to train fully due to injury, his presence has been felt around the camp.
Jesse Lingard loved spending time back together with Manchester United team-mate and friend Rashford, whose work off the field the is something the West Ham loanee is in awe of.
"He's done absolutely fantastic," he told the PA news agency this week. "I obviously grew up with Marcus and to see him from then to now is a huge change.
"At such a young age, he's so mature. He takes on a lot but he can handle it. He can do it on the pitch and off the pitch. He's done a fantastic job.
"Getting an MBE is a really special thing and you can only take your hat off to him. I tell him all the time how proud I am of how far he's come.
"He can do it on the pitch and off the pitch, which is the most important thing.
"To come back and see his face and have a bit of a laugh and banter with him has been a long time coming.
"But since I've been there (at West Ham) we've stayed in communication and we've spoke as well, so that friendship will always be there."