Within the last two decades, hemostasis factors have emerged as 'new' risk factors for coronary artery disease. Historical studies on the physiology of the sympathetic nervous system (SNS) attributed accelerated blood clotting to the components of the fight-flight response. Although this has not been demonstrated, exaggerated clotting related to SNS hyperactivity might confer an increased arterial thrombotic risk. This review outlines the effects of sympathetic activation as mimicked by adrenergic infusions and as elicited by mental stress and physical exercise, and the molecular mechanisms involved. A selective review of the pertinent literature was undertaken. Sympathetic activation provokes a simultaneous increase in molecules of both the coagulation and fibrinolysis pathways within minutes, resulting in net hypercoagulability as a part of normal human physiology. Catecholamines and adrenergic receptors interact to mediate hemostatic changes. Exaggerated procoagulant changes in individuals with a preexistent atherosclerotic disease, in those experiencing ongoing stressful life circumstances and in the physically untrained might confer a thrombotic threat with sympathetic activation. Initial evidence suggests that nonselective β-adrenergic blockade may attenuate clotting acceleration upon SNS activation. Prospective studies are needed to demonstrate whether exaggerated clotting as elicited by the SNS is associated with an increased risk of cardiovascular morbidity and mortality. If confirmed, intervention studies targeted at reducing this risk, for example with drugs, psychotherapy (including stress management) and regular physical exercise, would be warranted.