Stuart McCloskey and Josh van der Flier will make their Test debuts in Ireland's RBS 6 Nations clash with England at Twickenham on Saturday.
Battering ram centre McCloskey has replaced injured Ulster team-mate Jared Payne in Ireland's rejigged midfield, with Leinster's 22-year-old Van der Flier starting at openside flanker.
Connacht's 22-year-old lock Ultan Dillane could also make his Test bow off the bench, with Donnacha Ryan replacing concussion victim Mike McCarthy in Ireland's injury-hit second row.
New Zealand-born centre Payne has failed to beat the hamstring problem he suffered in the 10-9 defeat to France, causing Ireland boss Joe Schmidt to move Robbie Henshaw to 13 to accommodate the uncapped McCloskey.
McCloskey and Henshaw will form what is surely Ireland's biggest-ever centre pairing, with the 23-year-old Ulsterman having impressed hugely in PRO12 action this term.
McCloskey's Ulster team-mate Luke Marshall admitted Ravenhill's senior players mistook the 6ft 2ins, 17st powerhouse for a second row when he first pitched up for provincial training.
Now he has the chance to lay down a marker for a long-term spot in Ireland's midfield, provided he can master the nerves of a Twickenham debut.
Leinster's fast-developing flanker Van der Flier only signed his first senior contract in April, having made his provincial debut in March last year.
A natural scavenging openside, Ireland will hope Van der Flier will add an extra continuity edge against England's imposing pack.
Ireland have battled a daunting injury catalogue in their 16-16 draw with Wales and defeat in France, leaving their chances of an unprecedented third-straight Six Nations title all but done and dusted already.
The return to fitness of seasoned and potent props Cian Healy and Mike Ross ought to shore up their previously creaking scrum however.
Healy has beaten knee surgery to take a seat on the bench, while Ross has recovered sufficiently from his hamstring issue to start at tighthead.
Ireland starting XV: Kearney, Trimble, Henshaw, McCloskey, Earls, Sexton, Murray; McGrath, Best, Ross, Ryan, Toner, Stander, Van der Flier, Heaslip
Replacements: Strauss, Healy, White, Dillane, Ruddock, Reddan, Madigan, Zebo