The problems targeted by preventive interventions are often complex, embedded in multiple levels of social and environmental context, and span the developmental lifespan. Despite this appreciation for multiple levels and systems of influence, prevention science has yet to apply analytic approaches that can satisfactorily address the complexities with which it is faced. In this article, we introduce a systems science approach to problem solving and methods especially equipped to handle complex relationships and their evolution over time. Progress in prevention science may be significantly enhanced by applying approaches that can examine a wide array of complex systems interactions among biology, behavior, and environment that jointly yield unique combinations of developmental risk and protective factors and outcomes. To illustrate the potential utility of a systems science approach, we present examples of current prevention research challenges, and propose how to complement traditional methods and augment research objectives by applying systems science methodologies.