Until recently it was thought that no more than 50% of clinical coronary heart disease was explicable in terms of classical cardiac risk factors such as dyslipidemia, cigarette smoking, high blood pressure and diabetes. Recent epidemiological studies have increased our understanding of the mechanisms generating cardiac risk and have provided evidence indicating that psychosocial factors, including stress, recent major life events and the presence of depressive illness are involved here, “triggering” clinical cardiovascular events, and possibly also contributing to hypertension and atherosclerosis development. While the underlying mechanisms at play are most likely multi factorial in origin, involving the autonomic nervous system, platelet activation, thrombogenesis and endothelial dysfunction, recent work by us and others clearly indicates involvement of the sympathetic nervous system. Using clinical models of stress, including depression, panic disorder and hypertension, we have documented disturbances in the properties of sympathetic nerve firing, reduced function of the noradrenaline transporter and elevated noradrenaline spillover to plasma. In patients with severe hypertension resistant to therapy, aspects of health related quality of life and symptoms of depression were improved following renal denervation. Given that strategies for preventive therapy for stress-related cardiovascular disease remain largely unformulated, future research should focus on generating a better understanding of the neurobiology of psychogenic heart disease as a basis for the development of rational and effective treatment.