Prime Minister Theresa May will be forced into making another Cabinet reshuffle following the resignation of Home Secretary Amber Rudd on Sunday evening.
Ms Rudd became the fifth departure from the Cabinet since last year's snap General Election, after admitting she had "inadvertently" misled MPs over the existence of targets for removing illegal immigrants.
The Hastings and Rye MP stepped down the evening before she was due to make a statement in the House of Commons on the targets and illegal migration, as she faced increasing pressure over the handling of the Windrush "scandal".
Her resignation letter - in which she took "full responsibility" for not being aware of the existence of targets - follows the resignations of former defence secretary Sir Michael Fallon, Priti Patel as international development secretary, Damian Green as first minister and James Brokenshire, who left his role as Northern Ireland secretary on health grounds.
Mrs May said she was "very sorry" to see her successor as home secretary leave the post, while Ms Rudd's opposite number Diane Abbott said she had "done the right thing".
The pressure had been building on the former banker ever since the emergence of the "appalling" treatment of Caribbean immigrants to the UK between the 1940s and 1970s - the so-called Windrush generation.
Concerns had been raised about the immigration status of the Windrush generation and there had been stories of people being forced to prove their near-continuous presence in the country in order to prove they were here legally.
Ms Rudd referred to the Windrush "scandal" in her two-page resignation letter, admitting that people with a right to live in the UK had not always been treated "fairly and and humanely".
Opposition parties said she was paying the price for Mrs May's "hostile environment" policy towards illegal immigrants when she was Home Secretary which had led to people being wrongly stripped of their rights and threatened with deportation.
Ms Abbott said: "This was inevitable, the only surprise is that it took so long.
"The architect of this crisis, Theresa May, must now step forward to give a full and honest account of how this inexcusable situation happened on her watch."
Vince Cable, the leader of the Liberal Democrats, said Remainer Ms Rudd could cause Theresa May a headache from the backbenches with her views on Brexit.
He told BBC Radio 4's Westminster Hour: "I think here there were some very serious misjudgements and that's why she's had to go.
"I think the fact that Amber Rudd, Justine Greening and Dominic Grieve, others - very serious, highly respected figures - are out there, ranging freely - I would have thought would be a source of considerable headache to Theresa May and her more Brexit-oriented colleagues."
Ms Rudd's decision to stand down will come as a major blow to Mrs May who publicly declared her "full confidence" in her as recently as Friday.
It will also upset the delicate balance within the Cabinet between Leavers and Remainers ahead of a crucial meeting of the Brexit "war cabinet" on Wednesday to discuss Britain's future customs relationship with the EU.
Environment Secretary Michael Gove - one of the Cabinet's leading Brexiteers - was being touted as the front runner to replace her at the Home Office, with Sajid Javid also listed as being among the favourites.
Ms Rudd had appeared to be prepared to ride out the storm announcing her intention to come to the Commons on Monday to answer MPs' "legitimate questions" about the removals targets.
She had previously apologised in the House for the "appalling" treatment of the Windrush veterans, announcing a taskforce to resolve their immigration status as quickly as possible.
However, she was criticised for saying the Home Office was "too concerned with policy and strategy and sometimes loses sight of the individual", prompting accusations that she was trying to put the blame on civil servants.
Her latest difficulties began on Wednesday when she told the Commons Home Affairs Committee that the Home Office did not have targets for removals.
The following day, however, she returned to the House to admit that Immigration Enforcement managers did use "local targets" but she said they were "not published targets against which performance was assessed".
The pressure then ratcheted up on Friday with the leak of a Home Office memo, which referred to a target of 2,800 enforced returns for 2017-18, and the progress towards a 10% increase in enforced returns "which we promised the Home Secretary earlier this year".
In a series of late night tweets, Ms Rudd said she had not seen the memo - even though it was copied to her office - but admitted that she should have been aware of the targets.
Her position was further weakened over the weekend, however, when former immigration minister Brandon Lewis - now the Conservative Party chairman - disclosed they had held weekly meetings to discuss her plans to increase the numbers of removals, although he insisted they did not discuss detailed targets or numbers.