The sympathetic nervous system (SNS) is activated in patients with heart failure. Hemodynamic and metabolic abnormalities probably serve as the afferent stimulus for this response. This chronic activation is accompanied by an attenuation of reflex responsiveness to unloading of the central baroreceptors and mechanoreceptors. Loss of the buffering capacity of these afferent receptors may contribute to the sustained SNS stimulation. The renin-angiotensin system is uncoupled from the SNS, probably because the intrarenal mechanisms subserving renin release are preserved. Chronic activation of the SNS may contribute to disturbed hemodynamics as well as to long-term structural changes that may influence the natural history of the syndrome. A relation between plasma norepinephrine and mortality raises the possibility of a direct adverse effect of SNS activation on survival. Therapeutic approaches to inhibit the SNS include agents that block receptors, enhance the response to baroreceptor loading, inhibit presynaptic norepinephrine release, or act centrally to inhibit sympathetic outflow. The benefit-to-risk ratio for each of these possible interventions needs to be assessed in controlled long-term trials.