Whereas the earlier conceptual targets of heart failure therapy, such as the cardio-renal and hemodynamic models, all fulfilled the basic needs of symptomatic relief and hemodynamic improvement, only the neurohormonal model has provided an effective target to address symptom relief in concert with survival benefits. Recent data allude to a disease-modifying effect of angiotensin-converting enzyme inhibitors (ACE-Is) in retarding the new development of heart failure in high-risk populations. Angiotensin receptor antagonists (ARBs) have not been demonstrated to be superior to ACE-Is and their value in achieving incremental benefits in addition to ACE-Is is limited to scenarios in which &bgr;-adrenergic receptor blocker therapy is not applicable. &bgr;-Adrenergic receptor blockade in addition to ACE inhibition offers incremental benefits that are achieved early and are beneficial in most stages of severity except in the presence of overt decompensation. Unlike ACE-Is, &bgr;-adrenergic receptor blockers cannot be construed as a class but are heterogeneous in their therapeutic response.