Therapy for heart failure has traditionally been directed to such short-term functional abnormalities as low cardiac output, high filling pressures, and fluid retention. More recently, it has become clear that therapy must also inhibit the proliferative responses that contribute to the progressive deterioration of the failing heart. That heart failure is more than a hemodynamic disorder became apparent when clinical trials showed that drugs that improve such functional abnormalities as high venous pressure and low cardiac output failed to improve long-term prognosis. Most vasodilators, in spite of alleviating short-term problems caused by excessive afterload, increase long-term mortality; the notable exceptions are ACE inhibitors, the ability of which to prolong survival and inhibit remodeling can be attributed to inhibition of proliferative signaling. Other clinical trials showed that inotropic drugs, while providing immediate relief of symptoms, generally shorten long-term survival, whereas β-adrenergic receptor blockers, which inhibit proliferative signaling by norepinephrine, improve prognosis. These findings can be explained by crossovers between functional and proliferative signaling, among the most important of which is the ability of neurohumoral mediators, such as norepinephrine and angiotensin II, to stimulate maladaptive hypertrophy, remodeling, apoptosis and other deleterious proliferative responses in the failing heart. The emerging understanding of the role of cytoskeletal and cell adhesion molecules in activating maladaptive proliferative responses suggests additional targets for therapy, and the rapid pace of discovery in molecular biology promises additional opportunities to inhibit this abnormal signaling, which causes progressive ventricular dilatation (remodeling) and cardiac cell death, now recognized to be major problems in this syndrome. (Circ J 2002; 66: 225 - 231)