In his resignation statement, Mr Cain confirmed he had been offered a promotion to the key position of the Prime Minister’s chief of staff.
His departure sparked speculation he could be followed by Dominic Cummings, the Prime Minister’s top adviser seen as the most powerful figure in No 10. The two men had worked together on the 2016 EU referendum campaign fronted by Mr Johnson and are regarded as close political allies.
But while Mr Cummings was said to be unhappy at the way his friend had been treated, it was reported he had decided to stay on for now to work on the Government’s response to the coronavirus – in particular the acceleration of the mass testing programme.
Here is everything you need to know:
Who is Lee Cain?
Lee Cain began his career as a tabloid journalist, working for the Sun and Mail on Sunday before moving to the Mirror.
While working at the Mirror, he dressed up as a chicken and followed David Cameron around on the 2010 general election campaign trail.
He went on to become head of communications at the the Vote Leave campaign, where he worked closely with Mr Cummings. After the Brexit referendum, he worked as a special adviser for Boris Johnson at the Foreign Office.
He stuck with Mr Johnson when he quit two years later over Theresa May’s proposed Brexit deal and worked on his campaign to succeed her as Tory leader.
When Mr Johnson became Prime Minister, Mr Cain became his head of communications.
Following the announcement of Mr Cain’s resignation, Mr Johnson said that he had been “a good friend and ally” and would be “much missed”.
“I want to thank Lee for his extraordinary service to the Government over the last four years,” he said.
“He has been a true ally and friend and I am very glad that he will remain director of communications until the new year and to help restructure the operation.”
Why did he resign?
The sudden announcement of Mr Cain’s resignation came less than 24 hours after reports that he would become the Prime Minister’s chief of staff.
In his resignation statement, Mr Cain confirmed he had been offered the promotion and that he had made the decision to quit after “careful consideration”.
The move to place him as a chief of staff– which would have meant he was one of just a handful of people in No 10 with direct one-to-one access to Mr Johnson – was seen as entrenching the grip of the Vote Leave faction on the Downing Street operation.
However it ran into immediate resistance, with Mr Johnson’s fiancee Carrie Symonds – who has clashed in the past with Mr Cummings – reportedly strongly opposed to the appointment.
Allegra Stratton, the former TV journalist brought in to host televised No 10 news conferences from next year, was also said to have objected to the appointment.
What does his resignation mean?
The latest manoeuvrings come amid growing unhappiness among increasing numbers of Conservative MPs at the performance of No 10 and its handling of the coronavirus outbreak.
Sir Geoffrey Clifton-Brown, a senior member of the influential Tory backbench 1922 Committee, said Mr Johnson needed someone who could act as a link with the party in Parliament.
“I think it is essential for the Prime Minister to have a chief of staff. Somebody we can get hold of if we really need to,” he said.
Former Tory minister Jake Berry said the Prime Minister was “stamping his Johnsonian authority” on Downing Street.
The MP for Rossendale and Darwen told ITV’s Good Morning Britain: “The departure of Lee Cain does show, I think, that the Prime Minister is taking back control of his government.
“He’s moving from a campaigning operation to an operation solely focused on good government. I think it’s a good move for the Prime Minister.
“As we go past that grim milestone, as you say, of 50,000 deaths from this appalling disease, it’s high time, I think, that there was a bit of a change of guard in Number 10.”Mr Cain is the latest in a series of Government resignations.
Who else has resigned under Boris Johnson?
Jonathan Slater, the permanent secretary at the Department for Education, stood down when Mr Johnson “concluded that there is a need for fresh official leadership” after the A-Level results controversy.
Sir Mark Sedwill announced his departure from the role of Cabinet Secretary in June amid reports of clashes with Mr Cummings.
He has been replaced as the country’s top civil servant by Simon Case, and said in July that “demoralising” anonymous criticism of officials has “risen in the last few years”.
The Foreign Office’s most senior civil servant, Sir Simon McDonald, seen as a Brexit critic, was told he had to step down before the department was merged with the Department for International Development (DfID).
After he stepped down in June, it was announced in early August that Sir Philip Barton had been appointed as the senior civil servant chosen to head the new Foreign, Commonwealth and Development Office.
In February this year, the top civil servant at the Home Office, Sir Philip Rutnam, resigned, accusing Home Secretary Priti Patel of bullying.
Sir Jonathan Jones reportedly left the Attorney General’s office on September due to a dispute with Downing Street over concerns the Prime Minister wanted to row back on parts of the Brexit deal relating to Northern Ireland.