Drug policy often comprises efforts to reduce the supply of drugs, to provide health and social services to addicted individuals, and to prevent the development of addiction in the first place. The last of these efforts—prevention—is the subject of this paper. The scientific literature on drug policy offers some insights on the relative effectiveness and cost-effectiveness of different strategies for preventing traditional opioid misuse and related harm. But these insights don’t apply perfectly to the current opioid crisis in the U.S. and Canada, due to many important differences between today’s epidemic and those of the past (e.g., heroin in the 1960s and 1970s). School-based universal primary prevention programs, for example, will probably remain only modestly effective, mainly because it is mostly adults, rather than adolescents, who initiate opioid use through prescription drugs. However, there are new opportunities for prevention, including promoting safer opioid prescribing, and issuing public health warnings about fentanyl’s dangers and the need to keep prescription opioids locked up.