Cipriani and Rees were hoping to be able to impress England coach Martin Johnson before the November Tests
Wasps duo Danny Cipriani and Tom Rees have both been ruled out of England's autumn Test series through injury.
Fly-half Cipriani suffered a small hairline fracture to his right fibula when taking a blow to his knee during the victory over Northampton on Sunday.
He is currently on crutches and is expected to be out for six weeks.
Flanker Rees, who suffered a tear to his shoulder joint in April, underwent a second operation this week and will be sidelined for four months.
The news means the Wasps captain, who has won 15 England caps, is now a serious doubt for the start of England's 2010 Six Nations campaign against Wales on 6 February.
The disappointment of the delay in a return to fitness is secondary to Tom's health, comfort, and long-term career
Wasps rugby director Tony Hanks
Rees has had a frustrating time with injury since making his England debut in 2007.
He missed the 2009 Six Nations after tearing a medial ligament in his knee and although he returned for the end of the domestic season, he damaged his shoulder against Bristol.
The injury ruled him out of the England and the British and Irish Lions tours as the 25-year-old underwent his first operation in July.
At the start of October Wasps said Rees had reached "a plateau in his rehabilitation", and following consultation with medical staff at the club and England, a decision was made this week to have further surgery in order to "preserve the longevity of his career".
"This is not a decision that has been taken lightly by Tom or the club," said Wasps rugby director Tony Hanks.
"However the disappointment of the delay in a return to fitness is secondary to Tom's health, comfort, and long-term career.
"All parties believe that this is the best option for Tom and he will of course have the full support of the club through this difficult and frustrating time."
Cipriani is currently a part of England's second-tier Saxons squad, having missed out on a place in manager Martin Johnson's elite squad.
But with Johnson suffering a series of injuries to his backline, the 21-year-old - who can also play at full-back - would have been one of the players considered for promotion to the senior squad.
England start with the visit of Australia on 7 November, then face Argentina and New Zealand at Twickenham over the following two weekends.
London Irish full-back Delon Armitage and Brive inside centre Riki Flutey will miss the Tests while Leicester fly-halves Toby Flood (ruptured Achilles) and Sam Vesty (hamstring) are only expected to return to action for the Tigers in November.
Saxons and Harlequins centre Jordan Turner-Hall, who was a possible contender to replace Flutey, is also out, leaving Northampton's Shane Geraghty as the favourite to fill the 12 shirt against the Wallabies.
There are also concerns over centre Mike Tindall and full-back Olly Morgan after they both strained hamstrings in the league victory at Leeds on Sunday.
With Flood injured, Toulon's Jonny Wilkinson is expected to take the fly-half role with Tindall if fit, Brive's Jamie Noon, Dan Hipkiss of Leicester and Sale's Mathew Tait the other midfield candidates.
Northampton's Ben Foden, Morgan, and wings Ugo Monye and Mark Cueto, who have both played at full-back, are the contenders for the 15 shirt.