Natriuretic peptides play a crucial role in maintaining cardiovascular homeostasis. Among their properties are vasodilation, natriuresis, diuresis, and inhibition of cardiac remodeling. As heart failure progresses, however, natriuretic peptides fail to compensate. Knowledge of their processing and signaling pathways has guided the development of pharmacological therapies aimed at bolstering their effects. The drugs that have achieved the most clinical success have also stirred the most controversy. Nesiritide, the synthetic B-type natriuretic peptide, yielded significant symptomatic relief and improved haemodynamics but its use was plagued with questions surrounding its possibly harmful impact on renal function. More recently, compounds containing inhibitors of neprilysin, the enzyme responsible for degrading natriuretic peptides, have demonstrated morbidity and mortality benefit, but have also been linked to possible negative side effects. Clearly, potentiating the actions of natriuretic peptides for the benefit of patients is not as simple as just raising their serum concentration. This article reviews the current understanding of the compensatory actions of cardiac natriuretic peptides in heart failure and how this knowledge is revolutionizing heart failure therapy.