The article describes a prevention science approach to impacting population health. We use activities of the Missouri Prevention Science Institute that address youth mental health concerns with a public health approach to illustrate the approach. In particular, we focus on several lessons that may be relevant for advancing the success of prevention and health promotion scholars in addressing major societal problems: connecting small ideas to big solutions, matching intervention targets with goals, developing reliable and systemic monitoring data streams, ensuring data and prevention efforts account for cultural context, and helping people/systems change.