This article provides a selective review of the effects of psychosocial factors and responses to acute mental stress on the onset of acute coronary syndromes. The literature suggests that the relationship between the anatomical severity of coronary artery disease (CAD) and likelihood of subsequent cardiac events, such as myocardial infarction, is not linear. Furthermore, evidence will be provided that the age-dependent associations between psychosocial factors and risk of cardiac events is at least in part mediated through the severity of underlying CAD. Finally, research will be summarized that supports the importance of both chronic psychosocial factors (e.g., low socioeconomic status and/or high hostility) and episodic psychological distress syndromes, such as vital exhaustion and depression. In reviewing this literature, two perspectives will be focused on: (1) the relationship between psychosocial factors and progressive CAD; and (2) the evidence concerning underlying pathophysiological mechanisms.