Baroness Warsi has resigned from the government, on a day in which the crisis in Gaza sent shockwaves through the Conservative party.
As Westminster reeled from her shock resignation, London mayor Boris Johnson said Israel's actions had been "disproportionate", "ugly" and "tragic".
In a very strongly worded letter to the prime minister, Warsi said:
"Our approach and language during the current crisis in Gaza is morally indefensible, is not in Britain's national interest, and will have a long term detrimental impact on our reputation internationally and domestically.
"I believe our approach in relation to the current conflict is neither consistent with our values, specifically our commitment to the rule of law and our long history of support for international justice."
She then raised fears that Britain's foreign policy and home affairs departments were unprepared for the repercussions of the Gaza crisis – both at home and abroad.
"In many ways the absence of the experience and expertise of colleagues like Ken Clarke and Dominic Grieves has over the last few weeks become very apparent.
"Early evidence from the Home Office and others shows the fallout from the current conflict and potential for the crisis in Gaza and our response to it becoming a basis for radicalisation could have consequences for us for years to come."
"From both Eric [Pickles] and William [Hague] I learnt the art of reconciling passion and idealism with pragmatism and realism, but I always said that long after life in politics I must be able to live with myself for the decisions I took or the decisions I supported.
"By staying in government at this time I do not feel I can be sure of that."
The resignation of the Foreign Office minister will be a huge embarrassment for Cameron, who was warned recently that centrist Tories were uncomfortable with his unwavering support for Israel despite the extent of civilian casualties in Gaza.
The announcement, which came while the prime minister was out the country, took Westminster by surprise.
"It's the first I have heard of it," Nick Clegg said, when he was asked a question about it after a speech on immigration.
The deputy prime minister said it was "an open secret" that there are different views in government.
George Osborne called it a "disappointing and frankly unnecessary decision".
He added: "We want restraint on all sides, we want a ceasefire on all sides."
In his reply Cameron pointedly observers that Warsi did not notify him of her decision before announcng it.
"Thank you for your letter today, in which you set out your reasons for resigning from the government. I was sorry to receive this," he wrote.
"I realise that this must not have been an easy decision for you to make and very much regret that we were not able to speak about your decision beforehand."
Warsi had been criticising Israeli policy in increasingly harsh terms recently.
On 21 July, she tweeted: "The killing of innocent civilians must stop. Need immediate ceasefire in Gaza. Leadership required on both sides to stop this suffering."
Three days later she added: "Can people stop trying to justify the killing of children. Whatever our politics there can never be justification, surely only regret Gaza."
The loss of the Britain's first female Muslim Cabinet member will be a major blow for Cameron, coming soon after a reshuffle in which he attempted have a more diverse set of faces in government.
The prime minister has repeatedly insisted that Hamas is responsible for the Israeli military operation in Gaza and that the quickest way to end the fighting was for Hamas to stop firing rockets.
The argument prompted groans of disbelief from Labour MPs when Cameron made it in the Commons a few weeks ago, but the response has become far more intense since then, as images of wounded and dead children have dominated news bulletins.
Cameron issued his harshest words against Israel yet yesterday when he backed the UN's right to express criticism of the country for its attack on a third UN school in Gaza.
But he refused to reiterate the words of UN secretary general Ban Ki-moon, who described it as a "moral outrage and a criminal act".
Margot James, No.10 policy board adviser and aide to William Hague, and Peter Bottomley, former Northern Ireland minister, have both also criticised the Israeli response.
Some believe Cameron was stung by the angry response from some Tory donors when he criticised Israel's attack on Lebanon in 2006.
Back then, he criticised Israel's approach as "disproportionate" and attacked Tony Blair for not doing the same.
"Elements of the Israeli response were disproportionate and I think it was right to say that, and I think the prime minister should have said that," he told the BBC.
"I don't think it should be seen as an unfair criticism of Israel. It is just a statement of the fact. Britain is a friend of Israel, yes, and a friend of the US, but in both cases, we should be candid friends and we shouldn't be scared of saying to our friends when we think they are making mistakes or doing the wrong thing."
But the message from Cameron's allies has been very different now he is in government. Yesterday, justice secretary Chris Grayling attacked Ed Miliband for speaking out about the attack.
"I think we in Britain have to be enormously careful to try and work in a way that encourages a ceasefire, encourages an end to the action on both sides," he said.
"I don't think it helps if we make strong comments that are going to put us in less of a position to do that."
Downing Street accused Miliband of "playing politics" with the issue, after he branded the Israeli attack "wrong and unjustifiable".
He added: "The prime minister is wrong not to have opposed Israel's incursion into Gaza.
"And his silence on the killing of hundreds of innocent Palestinian civilians caused by Israel's military action will be inexplicable to people across Britain and internationally."
Baroness Warsi, a solicitor of Pakistani descent, grew up in Dewsbury, West Yorkshire. She worked for the Crown Prosecution Service and then set up her own legal practice before entering politics.
Downing Street released a statement saying: "The prime minister regrets that Baroness Warsi has decided to stand down and is grateful for the excellent work that she has done both as a minister and in opposition.
"Our policy has always been consistently clear - the situation in Gaza is intolerable and we've urged both sides to agree to an immediate and unconditional ceasefire."