Andy Burnham has announced he is leaving Jeremy Corbyn's shadow cabinet to focus on his bid to become Greater Manchester's mayor.
The shadow home secretary said he had asked the Labour leader to "plan a new shadow cabinet without me".
In his speech at the Labour conference in Liverpool, Mr Burnham said he had "given my all" to the party and had "always put its interests above those of factions and personalities".
The former leadership contender is hoping to be elected as the new mayor for Greater Manchester in 2017.
He said: "This is my 10th conference speaking to you as a cabinet or shadow cabinet minister. And it will be my last.
"It is time for me to turn my full focus to Greater Manchester. That's why I can tell you all first today that I have asked Jeremy to plan a new shadow cabinet without me, although I will of course stay until it is in place.
"I have given my all to this party and always put its interests above those of factions and personalities. And I have given exactly the same loyalty to all four of the Labour leaders I have served.
"Out there, there's a demand for big changes in the way this country is run. This party should be the voice for that change. So that's why I am ready to leave Westminster.
"It's time to make a change, to challenge the status quo from the outside. It's time to get the voice of the North heard like it has never been heard before."
The chair of the women's Parliamentary Labour Party, Jess Phillips, suggested Mr Corbyn could take the opportunity of Mr Burnham's departure to appoint a female shadow home secretary.
"Fond farewell and thank you to Andy Burnham as shadow home secretary. Great chance for Jeremy to even up women in four Great Offices of State 50/50," tweeted the Birmingham Yardley MP.
Shadow minister for preventing abuse Sarah Champion said Mr Burnham's announcement was "deeply sad, but understandable", hailing him as "a remarkable man who I've been proud to serve with".
But Liberal Democrat chief whip Tom Brake said: "Only Andy Burnham can resign halfway through his own speech.
"I believe in politics there are weathervanes and signposts. Andy Burnham is the weathervane in a gale. He has had more views on immigration than I've had hot dinners.
"For a man who has spent his life facing both ways on this critical issue, his speech today takes the biscuit."
"No, it's not in any way a blow to Jeremy," he told BBC Radio 4's World At One programme.
"As he begins to think about his new team, it's right for me to say it's time for me to take a step back because I've been elected as Labour's candidate to be the first mayor of Greater Manchester.
"So I know it's the way of this world that everybody will say things like that but it just isn't true."