The resignation is not just significant for the government's immediate plans, but also is yet another vote in parliament that could reject the Brexit plan, leaving the whole project in a crisis without any clear resolution.
"Britain stands on the brink of the greatest crisis since the Second World War".
Earlier on Friday, the DUP accused the Prime Minister Theresa May of breaking promises over plans to avoid a hard border between Northern Ireland and the Republic of Ireland after Brexit. The "democratic thing to do is to give the public the final say", he argued.
"I think that MPs, MEPs too. will be looking at what that deal says", the Cabinet Office minister said.
Lib Dem leader Sir Vince Cable, whose party supports calls for a "People's Vote" on the final deal, said: "We warmly welcome Jo Johnson's support of the campaign to give the people the final say on the deal and a chance to exit from Brexit".
"The first option is the one the Government is proposing: an agreement that will leave our country economically weakened, with no say in the European Union rules it must follow and years of uncertainty for business".
"The second option is a "no deal" Brexit that I know as a transport minister will inflict untold damage on our nation".
He acknowledged that the Brexit negotiations "have at least united us in fraternal dismay".
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In a long statement, the former rail minister, who voted to remain in the 2016 referendum, said: 'I have today written to the Prime Minister asking her to accept my resignation from the Government.
The former Remainer has been unable to embrace the possibilities offered by a clean "No Deal" Brexit in which Britain would deal with the European Union as a third country on standard World Trade Organisation terms, however, claiming this would mean "chaos". The critique from Johnson underscores the travails that May faces in getting any Brexit divorce deal, which London and Brussels say is 95% done, approved by her own fractious party.
"Out of all the Johnsons I have known, he is the most reflective", he added.
Describing Mrs May's Brexit plan as "a bad mistake" he accused the Prime Minister of negotiating a deal which wasn't "anything like what was promised".
His brother Boris, who quit as foreign secretary in July, praised his decision, saying the brothers were "united in dismay" at the Prime Minister's handling of the negotiations.
The Orpington MP resigned as a transport minister, saying the country was "barrelling towards an incoherent Brexit" and called for another referendum.
He wrote: "Boundless admiration as ever for my brother Jo".