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.