Boris Johnson has resigned as Foreign Secretary amid a growing political crisis over the UK's Brexit strategy.
He is the second senior cabinet minister to quit within hours following Brexit Secretary David Davis's exit.
His departure came shortly before Theresa May began addressing Parliament about her new Brexit plan, which has angered many Conservative MPs.
She said she did not agree with the two ex-ministers about "the best way to honour" the result of the 2016 vote.
The BBC's political editor Laura Kuenssberg said Mr. Johnson's exit had turned an "embarrassing and difficult situation for the PM into potentially a full-blown crisis".
She said he was not any ordinary cabinet minister but was the "face" of the Leave campaign during the 2016 referendum and his departure would fuel speculation about a leadership challenge.
She said she had been told by a source that either Theresa May "dumps" the plan signed off at Chequers or "another minister will go, then another, then another, then another".
The UK is due to leave the European Union on 29 March 2019, but the two sides have yet to agree how trade will work between the UK and the EU afterwards.
There have been differences within the Conservatives over how far the UK should prioritize the economy by compromising on issues such as leaving the remit of the European Court of Justice and ending free movement of people.
Theresa May only has a majority in Parliament with the support of the 10 MPs from Northern Ireland's Democratic Unionist Party, so any split raises questions about whether her plan could survive a Commons vote. There have also been renewed questions about whether she will face a challenge to her position.
Speaking in a boisterous House of Commons, Mrs. May paid tribute to Mr. Johnson's "passion" in championing a global Britain after Brexit and Mr. Davis' work in steering through key Brexit legislation.
But she told MPs: "We do not agree on the best way to deliver our shared commitments to honour the result of the referendum."
Mrs. May told MPs that the plan agreed by the cabinet at Chequers was the basis of a "responsible and credible" offer to restart renegotiations with the EU.
She said she had listened to "every possible version" of Brexit over the past two years and what she was proposing was the "right Brexit" that would respect the referendum commitments on money, borders, and laws but also protect the economy and ensure a "smooth" departure.
But she warned that if the EU did not engage with her plan, there was a "serious risk" of the UK leaving in March 2019 without a deal in a "disorderly" manner.