Foreign Secretary Liz Truss has taken over the Brexit brief after Lord Frost dramatically quit the Cabinet.
Downing Street announced the top Tory - a potential leadership rival to Boris Johnson - would take over "with immediate effect".
Her first task will be to iron out the final details of the future relationship amid stalled negotiations with the European Union.
The Prime Minister will hope that Ms Truss's appointment will help to placate the mutinous ranks of Tory backbenchers.
Lord Frost - who negotiated Britain’s departure from the EU - reportedly resigned over the “political direction” of Mr Johnson’s government.
Ms Truss backed Remain but since the referendum she has pinned her political ambitions on becoming an ardent Brexit supporter.
She regularly polls as the most popular senior Tory among party members and could be a threat to the PM in his precarious position with his own MPs.
But Mr Johnson has put her in charge of one of thethorniest of issues which could leave her struggling to keep both Tory Brexiteers and the EU happy.
Brexiteer Chris Heaton-Harris will become Minister of State at the Foreign Office and will deputise for Ms Truss on the Brexit brief.
In his resignation letter Lord Frost, a hardline Brexiteer who was regarded in European capitals as a block on progress, spoke of his desire to see a "low-tax" economy.
But insiders suggested that the PM's willingness to compromise with Brussels to finally get his Brexit deal over the line was the final straw.
It comes just days after Britain formally dropped its demand that Europe’s highest court should have no legal role in the controversial Northern Ireland protocol.
Lord Frost's departure was described as a "devastating blow" for Mr Johnson by prominent Tory Brexiteer Andrew Bridgen.
Tory MP Peter Bone added: "That rebellion of 100 Conservative MPs was partly due to the fact that we want to see the PM move to a more Conservative agenda in future."
