The cardiac natriuretic peptides (NPs) family comprises three main peptides (ANP, BNP and CNP) which are provided with properties relevant for cardiovascular and fluid homeostasis. They produce their cardiovascular and renal effects through the binding with guanylyl cyclase (GC)-coupled receptors, namely NPR-A and NPR-B. The NPR-C and neutral endopeptidase (NEP) contribute to NPs clearance. NPs levels progressively increase in heart failure (HF), in parallel with deterioration of left ventricular function and increased cardiac wall stress. The marked involvement of NPs in HF makes them valuable diagnostic and prognostic biomarkers. In view of their therapeutic implications in HF, inhibition of NPs catabolism through NEP has been obtained with the development of ARNi which comprises Angiotensin II-AT1 receptor blocker (valsartan) and a NEP inhibitor (sacubitril). ARNi has been recently introduced for the treatment of HF with reduced ejection fraction.