England will rest Alastair Cook, James Anderson, Ian Bell, Stuart Broad and Graeme Swann for the forthcoming one-day international series with Australia.
Eoin Morgan will lead an experimental squad which includes five uncapped players: Chris Jordan, Jamie Overton, Michael Carberry, Gary Ballance and Boyd Rankin.
England will play a one-off match against Ireland in Dublin on September 3, followed by five ODIs against the Aussies starting at Headingley on September 6.
All-rounder Jordan has been a revelation since swapping Surrey for Sussex last winter and is one of the leading wicket-takers in county cricket this season.
Carberry's call-up is less of a surprise - the Hampshire opener has been in prolific form in limited overs cricket and is already in the England Twenty20 squad.
Yorkshire batsman Ballance, who was born in Zimbabwe, is viewed as a potential Ashes tourist this winter. After being tipped as the 'next Graeme Hick' as a teenager at Derbyshire, he is finally fulfilling his promise at Headingley.
And Warwickshire fast bowler Rankin is yet to play for England but has been in limited overs squads.
The call-up of Somerset youngster Overton is perhaps the biggest surprise. A fast bowling all-rounder, he has impressed in limited-overs cricket this summer and has played for England U19s and the Lions.
Kevin Pietersen, Joe Root and Jonathan Trott will miss the trip to Ireland but will rejoin the group for the Australia series.
Ballance, Nottinghamshire batsman James Taylor and Hampshire spinner Danny Briggs will drop out after the Ireland match to make way.
National selector Geoff Miller said: "Following a very intense period of cricket this summer we have decided to rest a number of senior players which will allow them to recover from a heavy workload over the last three months and to prepare for the tour of Australia which begins in eight weeks.
"This creates an excellent opportunity for players who have impressed in county cricket and for England Lions recently to test themselves at international level as we continue to build a squad ahead of the ICC Cricket World Cup, which is less than 18 months away.
"There are a number of very experienced one-day players in the squad alongside players who are new to international cricket and we are expecting a very tough challenge both from a strong Ireland side and then from Australia in what will no doubt be a very competitive NatWest series."
With Australia also making a raft of changes for the series - only seven of their 18-man squad played in the Ashes - both countries clearly have their eye on the return Ashes series this winter, which starts on October 31 with a thee-day match against Western Australia.
Cook, Anderson, Bell, Broad and Swann have been almost ever present throughout as England regained the Ashes, reached the final of the Champions Trophy and beat New Zealand 2-0 in their home Test series.
It will be the first time Cook has been rested from a squad since he took over the Test captaincy 12 months ago.
England ODI squad vs Ireland
Eoin Morgan (Middlesex) (Capt), Gary Ballance (Yorkshire), Ravi Bopara (Essex), Danny Briggs (Hampshire), Jos Buttler (Somerset), Michael Carberry (Hampshire), Steven Finn (Middlesex), Chris Jordan (Sussex), Jamie Overton (Somerset), Boyd Rankin (Warwickshire), Ben Stokes (Durham), James Taylor (Nottinghamshire), James Tredwell (Kent), Luke Wright (Sussex)
England squad for NatWest ODI series
Eoin Morgan (Middlesex) (Capt), Ravi Bopara (Essex), Jos Buttler (Somerset), Michael Carberry (Hampshire), Steven Finn (Middlesex), Chris Jordan (Sussex), Jamie Overton (Somerset), Kevin Pietersen (Surrey), Boyd Rankin (Warwickshire), Joe Root (Yorkshire), Ben Stokes (Durham), James Tredwell (Kent), Jonathan Trott (Warwickshire), Luke Wright (Sussex)