The U.S. government’s current strategy of trying to restrict the supply of opioids for nonmedical uses is not working. While government efforts to reduce the supply has reduced both the amount of legally manufactured prescription opioids and the number of opioid prescriptions, deaths from opioid-related overdoses are nevertheless accelerating. Research shows that the increase is due, in large part, to substitution of illegal heroin and fentanyl for the now harder-to-get prescription opioids. Attempting to reduce overdose deaths by doubling down on this approach will not produce better results. Policymakers can reduce overdose deaths and other harms stemming from nonmedical use of opioids and other dangerous drugs by switching to a policy of harm-reduction. Harm reduction has a success record that prohibition cannot match and involves a range of public health options. Unlike prohibition, harm-reduction strategies begin with the realistic and nonjudgmental premise that there has never been, and will never be, a drug-free society. Akin to the credo of the medical profession — “First, do no harm” — harm reduction seeks to avoid measures that exacerbate the harm that prohibition already inflicts on nonmedical users and seeks to focus on the goal of reducing deaths and the spread of disease from drug use. This conference, featuring clinical and research experts in epidemiology, public health, addiction treatment, and harm reduction, will examine the record of various harm-reduction modalities in the developed world and will consider their potential for ameliorating the problems caused by drug prohibition.