The B-type natriuretic peptide (BNP), a member of the family of vasoactive peptides, has emerged as an important diagnostic, prognostic, and therapeutic tool in patients with heart failure (HF). The rapid incorporation into clinical practice of bioassays to BNP concentrations and pharmacological agents that augment the biological actions of this peptide such as nesiritide or vasopeptidase inhibitors has shown the potential for translational research to improve patient care. Despite the indirect evidence in support of a potential benefit from raising BNP, accumulating evidence suggests that simply increasing the amount of circulating BNP does not necessarily confer cardiovascular benefits in patient with HF. Moreover, in experimental HF, the response to treatments targeting specific natriuretic peptide receptors (NPRs) signaling seems to be attenuated. A better understanding of the NPRs signaling in HF would be clinically relevant and thus required, in order to devise strategies to develop novel agents and technologies that directly target this signaling pathway.