Roisin Shortall has resigned as junior minister for health, over what she described as a "lack of support for the reforms in the Programme for Government and the values which underpin it".
Ms Shortall has also resigned the Labour Party whip.
In a statement, Ms Shortall said the public has a right to expect that decisions on health infrastructure and staffing will be made in the public interest based on health need and not driven by other concerns.
She said that the decision comes after repeated and lengthy efforts to reach agreement on the implementation of the Programme for Government, both within the Department of Health and across Government.
Ms Shortall said: "It is with regret that I have today tendered my resignation as Minister of State at the Department of Health to An Taoiseach, Enda Kenny.
"I have also informed the Tánaiste, Eamon Gilmore, that I am resigning the Parliamentary Labour Party whip."
She said it was "no longer possible for me to fulfil my role as Minister of State for Primary Care".
Taoiseach and Tánaiste disappointed
The Taoiseach said he regretted Ms Shortall's decision and thanked her for her work, particularly in the area of dealing with alcohol abuse.
A spokesperson for the Tánaiste said Eamon Gilmore was "very disappointed" at Ms Shortall's resignation, saying that he very much appreciated her commitment to her role as Minister of State.
Mr Gilmore is in New York for a meeting of the United Nations General Assembly.
Through his spokesperson, he said the Labour Party is very much committed to the reform agenda in health and in the Programme for Government.
Labour’s Chief Whip Emmet Stagg said he regretted the resignation, saying the loss of a junior minister was a "serious matter" for the Government.
Several Labour backbenchers have also expressed regret at Ms Shortall's resignation on their Twitter accounts.
Dublin South-East's Kevin Humphreys said he was disappointed she felt she had to resign.
He said he had great respect for her and that she was leading the radical reform of health services needs.
Dominic Hannigan of Meath East said he was "very sad to see Roisin go".
Brendan Ryan, who shares the Dublin North constituency with James Reilly, said he was "so sorry" that she had resigned.
He added, that there was a lot of support for her within the party grassroots and the general public.
'Tense and difficult' meeting
Earlier this evening, Ms Shortall said she still had not received an explanation from Health Minister James Reilly as to what criteria were used to select an extra 15 sites for primary care centres, a spokesperson said.
They said yesterday's meeting between the two ministers had been "tense and difficult".
A newly released letter this evening from Minister Reilly to Ms Shortallexplained the reasons for expanding the list of 20 sites for proposed primary care centres to 35.
However, it does not explain the reasons for choosing what 15 locations would be added.