The natriuretic peptide system plays a key endogenous protective role in the pathophysiological process of heart failure. Cardiomyocytes reactively express and secrete natriuretic peptides in response to stimuli such as myocardial stretch. These peptides activate downstream signaling pathways through natriuretic peptide receptors, exerting a series of physiological effects including natriuresis and vasodilation, and are ultimately cleared from the circulation via natriuretic peptide clearance receptors or hydrolases. This cascade pathway provides multiple intervention targets for heart failure treatment, covering the entire process of natriuretic peptide synthesis, receptor activation, signal transduction, and degradation. Among these, some therapeutic strategies have achieved significant clinical progress: recombinant human natriuretic peptide drugs have been recommended as treatment options for acute heart failure in the guidelines or consensus statements of some countries and regions; sacubitril/valsartan, a fixed-dose combination of a neprilysin inhibitor and an angiotensin Ⅱ receptor antagonist, has become the international standard treatment regimen for heart failure with reduced ejection fraction (HFrEF); natriuretic peptide receptor agonists have also entered clinical trials and exhibited promising therapeutic potential. Based on these advances, this review addresses the clinical application and development of drugs targeting the natriuretic peptide system, and systematically summarizes the clinical evidence and research progress of agents acting at different intervention nodes, so as to inform the optimization of therapeutic strategies for heart failure.