The Stanford–Lancet Commission on the North American Opioid Crisis was formed in response to soaring opioid-related morbidity and mortality in the USA and Canada over the past 25 years. The Commission is supported by Stanford University and brings together diverse Stanford scholars and other leading experts across the USA and Canada, with the goals of understanding the opioid crisis, proposing solutions to the crisis domestically, and attempting to stop its spread internationally. Unlike some other Lancet Commissions, this one focuses on a long-entrenched problem that has already been well characterised, including in several reviews by the National Academies of Sciences, Engineering, and Medicine. This Commission therefore focused on developing a coherent, empirically grounded analysis of the causes of, and solutions, to the opioid crisis.