Heart failure is accompanied by sympathetic over-activity, which contributes to the pathophysiology and to poor prognosis. This paper reviews the mechanisms and potential therapy for sympathetic dysregulation in heart failure (HF). Several points are emphasized: (1) There is increased sympathetic activity to skeletal muscle, kidney, and heart, but not to skin, in HF. This information challenges the concept of generalized sympathetic activation in HF and suggests that the factors responsible for sympathetic activation result in a partitioning of excess sympathetic outflow to some but not all tissues and organs. (2) The sympathetic dysregulation appears to result from impairment in cardiac and arterial baroreceptor restraint on sympathetic activity, but this abnormality in baroreceptor function may result from abnormal humoral and/or ionic influences acting on baroreceptor endings or in the central nervous system and not from intrinsic structural abnormalities in baroreceptors. This distinction has potential therapeutic importance because abnormalities in humoral or ionic mechanisms would more likely lend themselves to therapeutic modulation. (3) Digitalis sensitizes cardiac and arterial baroreceptors and inhibits sympathetic nerve activity in patients with HF. This sympathoinhibitory influence of digitalis is maintained during chronic therapy. These observations support the concept that the therapeutic effects of digitalis include autonomic modulation in addition to positive inotropism. In a broader concept, these observations suggest that sympathetic modulation may represent an important target for drugs for treatment of heart failure.