The Centers for Disease Control and Prevention's (CDC's) Core Violence and Injury Prevention Program (Core) supports capacity of state violence and injury prevention programs to implement evidence-based interventions. Several Core-funded states prioritized prescription drug overdose (PDO) and leveraged their systems to identify and respond to the epidemic before specific PDO prevention funding was available through CDC. This article describes activities employed by Core-funded states early in the epidemic. Four case examples illustrate states' approaches within the context of their systems and partners. While Core funding is not sufficient to support a comprehensive PDO prevention program, having Core in place at the beginning of the emerging epidemic had critical implications for identifying the problem and developing systems that were later expanded as additional resources became available. Important components included staffing support to bolster programmatic and epidemiological capacity; diverse and collaborative partnerships; and use of surveillance and evidence-informed best practices to prioritize decision-making.