The opioid-driven public health crisis in North America has reached alarming proportions, contributing in 2016 to an estimated 64,000 deaths from drug overdoses in the US, and some 2,500 in Canada. The members of the Global Commission on Drug Policy, several of whom faced similar crises while occupying the highest levels of government in their own countries, share in this position paper their views and recommendations on how to mitigate this epidemic.