Recent evidence suggests that positive psychologic factors may be protective against coronary artery disease (CAD). We consider this possibility through a paradigm that explores three interrelated factors that may promote healthy psychologic functioning: vitality, emotional flexibility, and coping flexibility. Vitality is a positive and restorative emotional state that is associated with a sense of enthusiasm and energy. Flexibility is related both to the ability to regulate emotions effectively and cope effectively with challenging daily experiences. A variety of factors may diminish vitality, including chronic stress and negative emotions. Pathophysiologically, chronic stress and negative emotional states can both invoke a “chronic stress response” characterized by increased stimulation of the sympathetic nervous system and hypothalamic–pituitary–adrenal axis, with resultant peripheral effects, including augmented heart rate and blood pressure responsiveness and delayed recovery to stressful stimuli. Research indicates a wide array of stressful conditions—associated with either elements of relative inflexibility in psychologic functioning and/or relatively unabated stressful stimulation—that are associated with this type of exhausting hyperarousal. Conversely, new data suggest that positive psychologic factors, including positive emotions, optimism, and social support, may diminish physiological hyperresponsiveness and/or reduce adverse clinical event rates. Still other positive factors such as gratitude and altruistic behavior have been linked to a heightened sense of well-being but have not yet been tested for beneficial physiological effects. Pending further study, these observations could serve as the basis for expanding the potential behavioral interventions that may be used to assist patients with psychosocial risk factors for CAD.