Iain Duncan Smith said he is resigning as Work and Pensions Secretary blaming 'Treasury pressure to make cuts'.
The 61-year-old veteran Tory MP made the shock announcement tonight, just days after the Chancellor George Osborne revealed his latest Budget.
In a letter, Duncan Smith said: "I have for some time and rather reluctantly come to believe that the latest changes to benefits to the disabled and the context in which they've been made are, a compromise too far.
"While they are defensible in narrow terms, given the continuing deficit, they are not defensible in the way they were placed within a Budget that benefits higher earning taxpayers.
"They should have instead been part of a wider process to engage others in finding the best way to better focus resources on those most in need."
Read more: Will disability benefits be cut in 2016?
The Conservatives have come under heavy criticism for the disability cuts, even from members of their own party.
Earlier today is was reported that furious disability campaigners forced Osborne to abandon a planned photoshoot with fellow Tory MP and London mayoral candidateZac Goldsmith.
Placard-waving protesters screamed “blood on your hands” as the pair cut short the scheduled event after just two minutes at which Goldsmith hinted at a Government a U-turn.
It comes amid mounting anger at the Chancellor’s plans to slash vital disability benefits including the Personal Independence Payment (PIP) for those unable to wash or go to the toilet unaided.
Questioned at a train station in North London about the protesters a clearly rattled Mr Goldsmith, who is bidding to be the next London Mayor, said the cuts were “not a fait accompli”.
We'll be bringing you the very latest on this breaking story along with reaction as we get it.