The sexually transmitted infection (STI) epidemic among adolescents in the USA is inextricably tied to individual, psychosocial and cultural phenomena. Reconceptualizing the epidemic within an expanded socio-ecological framework may provide an opportunity to better confront its challenges. In this article, we use a socio-ecological framework to identify determinants of adolescents' sexual risk and protective behaviours as well as antecedents of their STI acquisition. The goal is to provide a synthesis of several discrete categories of research. Subsequently, we propose an integrated strategy that addresses the STI epidemic among adolescents by promoting a socio-ecological perspective in both basic research and intervention design. This approach may expand the knowledge base and facilitate the development of a broader array of intervention strategies, such as community-level interventions, policy initiatives, institutionally based programmes, and macro-level societal changes. Although there are inherent challenges associated with such an approach, the end result may have reciprocal and reinforcing effects designed to enhance the adoption and maintenance of STI-preventive practices among adolescents, and further reduce the rate of STIs.