The former Trade and Industry Secretary was one of a handful of Labour MPs who refused to sign Mr Brown's nomination papers in 2007, and he has used his position on the backbenches to launch well-timed challenges to the PM's leadership.
High-profile attacks on key Brown policies such as the "cynical" 50p income tax rate for top earners were combined with behind-the-scenes plotting with fellow former ministers like Charles Clarke who wanted a return to New Labour policies and a change of personnel at the top of the party.
He was widely reported to have been behind an attempt to force Mr Brown out by gathering Labour MPs' signatures on a letter earlier this year, although the alleged plot came to nothing.
Mr Byers' efforts to unseat Mr Brown came to a head in the days after the disastrous local and European elections in June, when he urged the PM to stand down at a stormy private meeting of the Parliamentary Labour Party, telling him he was leading the party to "humiliation and disgrace".
In public, he said Labour MPs should decide whether Mr Brown was "a winner or a loser" and in private he left no doubt what his judgment of the PM was.
He was recently reported to have pressed Lord Mandelson to tell Mr Brown he should hand over to another leader with a better chance of beating David Cameron.
Even before Mr Brown became Prime Minister, the North Tyneside MP was an "outrider" for the Blairite project on the backbenches, floating radical policy ideas - often involving greater private sector involvement in public services - which ministers were not yet ready to espouse in public.
He was a key member of Tony Blair's Cabinet from 1998 to 2002, brokering the sale of MG Rover to the Phoenix consortium and taking the nation's rail infrastructure back into public control.
But he will perhaps best be remembered for the rows which preceded his resignation from Government in 2002, after it emerged that his special adviser, Jo Moore, had sent an email telling press officers at the Transport Department that the September 11 terror attacks made it "a good day to bury bad news".
Ms Moore and director of communications Martin Sixsmith were later forced out when it emerged that Mr Sixsmith had warned her not to try to "bury" any more news on the day of Princess Margaret's funeral.
Mr Byers hung on for a few months longer, but eventually quit on the grounds that his continued presence in Government was damaging the Labour Party.
Born in Wolverhampton in 1953 and educated at Liverpool Polytechnic, Mr Byers was a law lecturer before entering politics as a councillor in North Tyneside in 1980.
He rose to be deputy leader of the Labour-controlled council from 1985 until his entry into Parliament as MP for Wallsend in 1992. He switched to North Tyneside as a result of boundary changes in 1997.
In his early days as a councillor, Mr Byers had flirted with the far-left, but as an MP he was firmly on the right of the party, becoming one of Mr Blair's closest lieutenants as he imposed New Labour policies.
He was made minister for school standards after Labour's 1997 victory, and swiftly moved into the Cabinet as Chief Secretary to the Treasury in 1998. Later that year, he was promoted to Trade and Industry Secretary after Peter Mandelson's shock resignation.
In that role, Mr Byers backed a rescue deal for MG Rover which saw a group of former managers buy the car manufacturer from BMW for £10.
In the wake of Rover's subsequent collapse, entrepreneur Jon Moulton blamed Mr Byers for blocking a takeover by his Alchemy consortium, but a report earlier this year did not single him out for criticism.
Following the 2001 general election, Mr Byers moved to the newly-created Department for Transport, Local Government and the Regions as Secretary of State. He was in fact, the only Secretary of State for Transport, Local Government and the Regions, as the unwieldy department was split up following his brief tenure.
Perhaps ironically for a politician on Labour's right-wing, his act of most lasting significance was to put the private company Railtrack into receivership in 2001, as it floundered in the aftermath of the Hatfield train crash, and hand it over responsibility for Britain's railway infrastructure to the not-for-dividend Network Rail.
His decision led to a lengthy court battle by shareholders who claimed they had not been properly compensated. The High Court rejected the shareholders' £150 million claim in 2005, but Mr Byers was later forced to apologise to MPs for making a misleading statement to Parliament over the affair.
Leaked details of MPs' expenses revealed earlier this year that Mr Byers, 56, had claimed £125,000 in second home allowances on a flat wholly owned by his partner of 22 years, Jan Cookson. He insisted he had not broken the rules, but he was later drenched with a soft drink sprayed on him by a constituent angered by the revelations.
His departure is not believed to be linked to the expenses scandal. After his fruitless efforts to change the direction of the Labour Government, it is thought that he did not relish the prospect of years of isolation in opposition and wanted to pursue opportunities in the private sector. He was recently reported to have taken up a position in a group lobbying for Ukrainian entry into the EU.
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