An extensive research literature in the behavioral sciences and medicine suggests that psychological and social factors may play a direct role in organic coronary artery disease (CAD) pathology. However, many in the medical and scientific community regard this evidence with skepticism. This chapter critically examines research on the impact of psychological and psychosocial factors on the development and outcome of coronary heart disease, with particular emphasis on studies employing verifiable outcomes of CAD morbidity or mortality. Five key variables identified as possible psychosocial risk factors for CAD are addressed: acute and chronic stress, hostility, depression, social support, and socioeconomic status. Evidence regarding the efficacy of psychosocial interventions is also presented. It is suggested that, taken as a whole, evidence for a psychological and social impact on CAD morbidity and mortality is convincing. However, continued progress in this area requires multidisciplinary research integrating expertise in cardiology and the behavioral sciences, and more effective efforts to communicate research findings to a biomedical audience.