Introduction: Since 1999, overdose deaths involving opioids have substantially increased. In 2016, 42,249 opioid-related deaths occurred a -27.7% increase from the previous year (Hedegaard et al., 2017). As the nation's public health agency, the Centers for Disease Control and Prevention (CDC) has been actively involved in efforts to prevent opioid misuse, opioid use disorder, and opioid overdose since 2014. One of CDC's three principal opioid overdose prevention programs, the Prevention for States (PfS) program, began funding 16 state partners in August 2015 and then expanded to fund a total of 29 states in March 2016. The PIS program aims to prevent opioid morbidity and mortality by implementing evidence-based strategies such as enhancing and maximizing prescription drug monitoring programs (PDMPs) and implementing community or health systems interventions. Methods: In this article, we will describe the origins of the PfS program, provide an overview of program strategies, and locate PfS strategies in the larger landscape of nation-wide opioid overdose prevention efforts advanced by other partners and stakeholders. To describe the implementation of PIS, we offer an iterative model of using information to inform strategy selection, implementation, and evaluation. This model is a product of our observations of program implementation over time and has emerged, post hoc, as a helpful framework for organizing our insights and reflections on the work. Results: For each step of the model, we provide examples of how CDC has supported funded state partners in these efforts. Lastly, we describe innovative facets of the program and implications for both ongoing and future programs. Practical applications: Opioid overdose morbidity and mortality continues to increase across the United States. Adoption of the strategies and the program implementation paradigm described in this article when implementing prevention activities could improve the ability of public health programs to reverse this trend. Published by Elsevier Ltd.