David Blunkett has said he is "deeply sorry" for the embarrassment he has caused Tony Blair, after he resigned as work and pensions secretary.
He said he was guilty of making a mistake on three occasions and was now "paying the price for it".
Tony Blair described Mr Blunkett as a "decent and honourable man".
Mr Blunkett quit after breaking the ministerial code of conduct over paid work he took while out of the Cabinet. John Hutton is to replace him.
Michael Howard said the events showed a "haemorrhage" of Mr Blair's authority.
Mr Blunkett was previously forced to step down as home secretary in December 2004.
At the centre of the recent controversy was Mr Blunkett's two-week directorship of DNA Bioscience before May's election, while he was out of the Cabinet.
Mr Blunkett broke ministerial rules by taking that job without consulting an independent committee which advises former ministers on whether they should take up jobs.
At a news conference in central London, Mr Blunkett told reporters he had been considering quitting since last week, but made his mind up to go on Wednesday "to protect the government".
He had been due to appear before the Commons work and pensions committee on Wednesday morning.
But instead he went to Downing Street to tell Mr Blair of his decision to resign.
"What I am clear about is that I have made a mistake," he said.
He should have consulted an advisory committee before taking up new jobs after leaving office for the first time in December, he said.
"Was I at fault not writing to the committee?" he asked. "Yes, I was. It was the same fault on three occasions arising from the same misunderstanding by me.
"I have to take the consequences of that, which is why I am standing down today."
'Blair is the target'
But he denied he had done anything wrong by buying shares in DNA Bioscience. "Having investments and holding shares in modern Britain is not a crime, declaring them is imperative," he said.
Mr Blunkett said after speaking to Mr Blair, "Tony asked me to stay".
It was only while travelling between Downing Street and Portcullis House, where he was due to appear before the work and pensions committee, that he could "smell and feel it was time to step away".
"I am deeply sorry for the embarrassment I have caused the prime minister," he said.
"It's the prime minister that some people wish to target. I wish to support him, I wish him to continue taking forward the modernisation."
He suggested that he had not yet sold his shares in DNA Bioscience, but would be consulting with his sons about what to do next.
One of the directors of DNA Bioscience, Lucy Siddiqi, has said she is stepping down because of the "intense" media attention on her and her family.
In the Commons, Mr Blair told MPs that none of the allegations against Mr Blunkett warranted his dismissal under the ministerial code.
"I could discover no impropriety or wrongdoing," he said.
'Seepage of authority'
The mistakes arose out of an "honest misunderstanding", said the prime minister, and Mr Blunkett had left office "with no stain of impropriety against him whatsoever".
But outgoing Tory leader Michael Howard dubbed Mr Blair a "lame duck" prime minister, adding that the week had seen the "seepage of his authority turn into a haemorrhage".
Mr Blunkett's decision to go came as it emerged that Lord Nolan, ex-chairman of the Committee on Standards in Public Life, had suggested Mr Blair should sack or demote Mr Blunkett.
Lord Nolan told the Yorkshire Post: "Blair should insist on ministers all round obeying the rules.
"I think that if anyone breaks the rules, they should be disciplined. Otherwise, there's no point having the rules."
Harry Harpham, Mr Blunkett's constituency agent, said the MP "had been hounded out of office" by a combination of pressure from the Conservative party and the press.
Shadow Commons leader Chris Grayling, who has written to Tony Blair on a number of occasions about Mr Blunkett's conduct, said his resignation had been "inevitable".
"I don't believe that you can systematically ignore the ministerial code," said Mr Grayling.
"Joining a company for two weeks during the general election campaign and becoming a director - people don't do that sort of thing.
"Through his own actions, he created huge question marks over his judgement."
Mr Blunkett stepped down as home secretary last year over claims his office had fast-tracked a visa application for his lover's former nanny.