The Vote Leave allies will work out their notice periods from home with Sir Edward Lister standing in as interim chief of staff pending a wide-ranging shake-up of Mr Johnson’s team.
But why did Mr Johnson’s right-hand-man leave so suddenly? And what does this mean for Number 10? Here’s what we know so far.
Cummings seen leaving Number 10 with boxes as he ‘quits with immediate effect’
Why did Cummings quit so abruptly?
The Sun reported there was a “shouty” confrontation between Mr Johnson and Mr Cummings over the ousting of Mr Cain and that a “livid” Prime Minister wanted both out “sooner rather than later”.
The BBC reported Mr Cummings’ departure had been brought forward given the “upset in the team” and that Mr Jonson wanted to “clear the air and move on”.
Despite the controversy surrounding the two departures, Mr Cummings has said his “position hasn’t changed since my January blog”, in which he said he hoped to be “largely redundant” by 2021.
But the Daily Telegraph said tensions within No 10 were running high, with Mr Cummings accused of briefing against the Prime Minister.
The newspaper reported Mr Cummings was said to have told colleagues Mr Johnson was “indecisive” and that he and Mr Cain relied on Cabinet Office minister Michael Gove for clarity.
It was also suggested the PM was angered by claims a faction headed by Mr Cummings and Mr Cain had been “briefing against him” and his fiancee Carrie Symonds.
According to the Daily Mail, tensions were raised further when the Prime Minister was shown “hostile texts” briefing against Miss Symonds, which had been forwarded to her.
Who will replace Cummings and Cain?
It is understood Mr Cummings, 48, and Mr Cain, 39, will still be employed until the middle of next month, with some reports suggesting Mr Cummings will work from home on projects such as mass testing.
Mr Cain is to be replaced as director of communications by James Slack, who is currently the Prime Minister’s official spokesman.
Lord Lister, who has served as Mr Johnson’s chief strategic advisor since July 2019, was announced as acting chief of staff until a permanent replacement for Mr Cummings can be found.
The formal title was out of use under Mr Cummings, who instead served as “chief adviser to the Prime Minister”.
What has the response been from Tory MPs?
Conservative backbenchers have urged No 10 to use the exit of the aide – whose mid-lockdown trip to Durham sealed his notoriety – as an opportunity to restore several important values in the relationship between No 10 and Tory MPs.
Senior Tory MP Sir Bernard Jenkin said it was time to restore “respect, integrity and trust” to the relationship, elements which had been “lacking in recent months”.
He said: “It is said… people ranging from Allegra (Stratton) – the new spokesman for the Prime Minister – right through to his (Mr Johnson’s) fiancee, Carrie, turned against him.
“The relationship with the Prime Minister fell off a cliff. And once that’s gone, it’s gone.”
Mr Davis, who was allegedly described as “thick as mince” and “lazy as a toad” by Mr Cummings when in the Cabinet in 2017, also branded the adviser’s style “confrontational” but added the PM had “relied on him” and “there are things he (Mr Cummings) was right about”.
On what could change, Mr Davis told BBC Breakfast: “Well the first thing is there are going to be some new staff in Number 10. He’s going to need a new chief of staff who has got to be fiercely efficient but not fiercely political. He’s got to find someone who doesn’t have their own agenda.
“Secondly, lots of my colleagues in Parliament are hoping for a new relationship with Parliament. More openness, more interaction with Parliament.”
Theresa May’s ex-chief of staff, Lord Gavin Barwell, also said the departure could lead to more harmonious relations between the Prime Minister and Tory MPs.
Referring to Mr Johnson, Lord Barwell told BBC Radio 4’s Today programme: “It feels to me that there’s an opportunity here for him to get his Downing Street operation more harmonious and more effective.
“To rebuild relations with Conservative MPs, the parliamentary party.
“And, perhaps, to set a less confrontational and more unifying tone, that is maybe more in tune with his natural instincts.”
Isn’t this all a big distraction for the Government?
Shadow health secretary Jonathan Ashworth has hit out at Downing Street for being “paralysed by the soap opera of these self-indulgent spin doctors” while the rest of the country buckles under the strain of the coronavirus pandemic.
“It’s pathetic,” Mr Ashworth said.
But Mr Slack, who will replace Mr Cain in the new year, insisted Mr Johnson is not being distracted from the national crisis by the row.
“What the Prime Minister and the Government are focused upon is taking every possible step to get this country through the coronavirus pandemic,” he said.