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Drawing from regional case study examples in Canada and the US, this article historically traces and politically re-maps the uneasy relationship between the autonomous political origins of harm reduction, contemporary public health policy, and the adoption of the biomedical model for addiction research and treatment in North America. Situated within a broader theoretical interrogation of the etiology of addiction, this study culminates in a politically engaged critique of traditional addiction research and drug/service user autonomy. Arguing that the founding philosophy and spirit of the harm reduction movement represents a fundamentally anarchist-inspired form of practice, this article concludes by considering tactics for reclaiming and re-politicizing the future of harm reduction in North America.