The goal of this research is to utilize a transdisciplinary framework to guide the selection of putative moderators of the effectiveness of an intervention to promote physical activity behavior adoption and maintenance in the context of a randomized controlled intervention trial. Effective interventions to increase physical activity are sorely needed, and one barrier to the identification and development of such interventions is the lack of research targeted at understanding both the mechanisms of intervention efficacy and for whom particular interventions are effective. The purpose of this paper is to outline our transdisciplinary approach to understanding individual differences in the effectiveness of a previously successful exercise promotion intervention. We explain the rationale for and operationalization of our framework, characteristics of the study to which we apply the framework, and planned analyses. By embracing a transdisciplinary orientation for individual differences important in the prediction of physical activity (spanning molecular approaches, animal models, human laboratory models, and social psychological models), we hope to have a better understanding of characteristics of individuals that are important in the adoption and maintenance of physical activity.