In one of the most public coalition spats in Britain, Liberal Democrat MP Norman Baker said working with UK Home Secretary Theresa May - from the Conservative-led coalition - was like "walking through mud".
"They have looked upon it as a Conservative department in a Conservative government, whereas in my view it's a coalition department in a coalition government," he told The Independent newspaper in an interview just before handing in his papers to party leader Nick Clegg.
There comes a point when you don't want to carry on walking through mud and you want to release yourself from that," he added.
Baker, who was the crime prevention minister in the Home Office, has had a number of clashes within the department over sweeping changes required in the UK's drugs policy, including decriminalisation.
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A recent Home Office report had concluded there was no obvious link between tough laws and levels of illegal drug use.
Baker's resignation is being seen as further evidence that relations are rapidly deteriorating within the coalition ahead of next year's general election.
"Despite these challenges, I am pleased with what I have been able to achieve, not least to have been the first minister with responsibility for drugs to have put prejudice aside and published an evidence-based approach to this important issue, despite repeated Conservative efforts to block release," he wrote in his resignation letter.