Pierre-Emerick Aubameyang and Alexandre Lacazette will both miss Arsenal's Premier League opener vs Brentford on Friday night in what is a huge blow to Mikel Arteta.
The Gunners begin their campaign in west London against one of the league's newly promoted sides.
Arsenal and Arteta need to begin strongly after what was a disappointing year last term.
But they will have to do so without two of their leading marksman, who combined for 32 goals last season.
In their final pre-season run out last weekend both players started against rivals Tottenham.
Aubameyang occupied his usual left wing spot whilst Lacazette led the line, but Arteta will now need to find replacements for them both, reports the Athletic's David Ornstein.
They join Thomas Partey, Eddie Nketiah and Gabriel on what is a lengthy list of absentees.
Nicolas Pepe remains an option in attack as do Gabriel Martinelli and Willian.
Bukayo Saka, who returned last week in the pre-season defeat at Tottenham, could also fill one of the attacking roles.
Arsenal are not expected to challenge for the top four, with very few, if any, predicting that they will finish above the two Manchester clubs, Chelsea or Liverpool.
Arteta was quizzed on the doubts around the club amid lengthy odds with the bookmakers.
He said: "I don’t know where they get that from.
"Hopefully we can prove them wrong. Last year it was six points (off fourth place). We need to be there.
"We can find excuses, other teams doing whatever. We have to find a way — our way — to do it with the tools we have."
The Gunners boss is not underestimating their opening opponents, who will play their first ever game in the Premier League, having praised their ethos.
"If you look historically at what they’ve done in the last few years there’s a very clear direction," he said.
"I think from top to bottom of the club they know what they want to do and they execute it really well. I think they will be a really tough opponent for every team in the Premier League.
"[I like] the clarity in what they do. They’ve been doing it for a long time together and you can see they have that fluidity and chemistry between them, and they believe that the plan they’ve put in place works for them. I think that’s a big strength for any team."
Arsenal did finish last season strongly, winning five games on the bounce, beating Chelsea along the way.
However their late surge was not enough and they finished in eighth, six points off fourth place, meaning they have no European football this term.
