Secondary prevention of adverse outcomes in patients with cardiopulmonary disease requires that patients become actively engaged in self-management efforts such as participation in physical activity or medication adherence. However, despite assiduous efforts to find strategies that help cardiovascular patients to adopt and maintain such behaviors, many studies of interventions designed to improve physical activity and adherence to medication have shown disappointing results. To this end, the Translational Behavioral Science Research Consortium was created by the National Heart, Lung, and Blood Institute to identify promising, but underutilized findings from basic behavioral science that might have potential application for translation to clinical populations where behavioral change has been refractory to standard intervention approaches. This paper describes the rationale and methods of a novel research project designed to test the efficacy of a behavioral intervention that combines constructs from two behavioral science theories (positive affect and self-affirmation) in order to help patients with coronary artery disease, asthma, and hypertension successfully change behaviors. The project consists of an intervention framed upon positive affect and self-affirmation and tested in three concurrent randomized controlled trials among three distinct populations. Each trial had a qualitative phase that served as a formative stage to inform the intervention; a pilot phase during which the feasibility of the intervention was tested and refined; and a randomized controlled phase conducted to investigate the effects of the interventions in these three patient groups.