This article presents a model that identifies effects of blood pressure variability (BPV) as a possible mechanism by which psychological/psychiatric factors and health behaviors confer increased risk of coronary artery disease (CAD) and acute coronary syndromes. Recent research in vascular biology and dynamics of coronary artery blood flow suggests that BPV may have pathogenic effects on the coronary endothelium, plaque formation, and plaque stability. Thus, BPV may be a risk factor for cardiovascular disease independent of mean arterial pressure. The model proposes that autonomic control of the heart exerts a buffering or inhibitory influence on oscillations in blood pressure. Established psychological/behavioral risk factors for CAD, such as depression, hostility, and anxiety, as well as physical deconditioning and aging, are associated with diminished autonomic control of the heart, which may disinhibit pathogenic BPV. Together, these data suggest a coherent, testable psychophysiological model of CAD. In this article, we review these data and make recommendations for research to examine the model.