Junior doctors began the first all-out strike in the history of the NHS on Tuesday - and the trainees and their supporters were out in full force on picket lines.
Jeremy Hunt appealed directly to medics on Monday not to withdraw emergency cover, which he said had particular risks for A&E departments, maternity and intensive care.
The impasse between the Government and the British Medical Association (BMA) prompted the industrial action, from 8am to 5pm on Tuesday and again on Wednesday.
It is the first time services such as A&E, maternity and intensive care have been affected during the dispute over a new contract, the Press Association reported.
Around the country, junior doctors and their supporters took to picket lines and there were a number of creative placards among them.
Speaking on BBC Breakfast, Hunt accused union leaders of trying to "blackmail" the Government with strike action.
He said he could only call a halt to the action "by abandoning a manifesto promise that the British people voted on" at last year's general election.
Despite an intense three days of letters back and forth and a phone call between Hunt and the head of the BMA on Monday, no agreement on a way forward was reached.
Hunt said he was motivated by a desire to improve weekend services in the NHS and told MPs that "no trade union" had the right to veto a government manifesto commitment to do so.
He said the disruption over the next two days is "unprecedented" but the NHS has made "exhaustive efforts" to ensure patient safety.
An Ipsos Mori poll for BBC News has found 57% support the doctors' cause while a quarter oppose it.
The majority still think the Government is most at fault for the dispute - but a rising number think the Government and doctors are equally to blame.
Public support for the all-out strike, where no emergency care is provided, appears to be higher than in January.
Labour leader Jeremy Corbyn joined junior doctors marching on Downing Street after earlier tweeting his support for them.
More than 125,000 appointments and operations have been cancelled and will need to be rearranged across England's hospitals as a result of the latest dispute.
The BMA has defended the walkout, repeating its stance that it would have called off the strike if Hunt agreed to lift his threat to impose the contract.
The head of the BMA, Mark Porter, told the BBC Radio 4 Today programme on Monday that the Government had "distorted" weekend death statistics, and stressed that emergency cover would be provided by consultants during the strike.
Responding to Hunt's claim that lives were being put at risk by the strike, he added: "The Health Secretary is trying to find some way to throw mud at the junior doctors of this country who have been providing weekend and night emergency cover since the NHS started."