The neurohumoral hypothesis provided the rationale for treating heart failure with angiotensin-converting enzyme (ACE) inhibitors, aldosterone blockers, and -blockers. Backed by the cytokine hypothesis, the case for incremental benefit from neurohumoral and cytokine blockade appeared made. However, the pendulum may have swung too far. Clinical trials are releasing evidence of hypotension, renal insufficiency, and critical loss of adrenergic support. ACE inhibitors and -blockers are already so successful that added treatments do not automatically confer added benefits. More is not necessarily better. Neurohormonal activation is, at least in part, a healthy response to the low cardiac output that defines heart failure. Although its partial blockade remains an effective treatment, we are only just beginning to understand why at the receptor, postreceptor, and cardiovascular cell type level...