Heart failure is a clinical syndrome associated with progressive cardiac, vascular, and renal dysfunction. Regardless of the initial injury, investigations have demonstrated that neurohormones play an important role in the complex multiorgan and cellular adaptations. Natriuretic peptides play a key role in this process, antagonizing the actions of the renin-angiotensin-aldosterone system, thus promoting vasodilatation and natriuresis. Other important physiologic properties of the natriuretic peptides are prolusitropic, sympathoinhibitory, antiproliferative, anti-ischemic, anti-inflammatory, and antioxidative. Administering exogenous natriuretic peptide is a US Food and Drug Administration-approved therapy for patients with advanced decompensated congestive heart failure. Also, measuring natriuretic peptide levels has diagnostic and prognostic value. More studies are needed to define the full potential of this unique family of endogenous peptides.