3 Abstract This playbook was created in response to the historic public health problem that the opioid epidemic poses for the United States, in particular by highlighting a variety of prevention-focused programs, initiatives and strategies – all of which we call plays – that are being attempted to “get upstream” of the crisis. The 11 plays in this document have been shown to be effective by evidence or are supported by expert opinion as helpful in preventing opioid use disorders. The plays are synopsized, along with additional relevant data about them, including the results of evaluations (where available) and links to resources to obtain further information. The playbook also provides background and context relating to the epidemic, as well as insights into why multi-sector collaboration, interoperability and information-sharing need to be critical elements of any effective effort to combat the crisis. Our objective is to increase awareness of the need for more prevention-related efforts; to provide ideas to jurisdictions and organizations about “plays” they might wish consider; and to support groups at the local, state and federal levels that are collaborating to reduce the incidence of opioid use disorders.