The discovery of natriuretic peptides represents one of the most crucial discoveries in cardiovascular medicine, shedding light on the endocrine properties of the heart. Natriuretic peptides are activated in heart failure (HF), and they play an important role in cardioprotection. Atrial natriuretic peptide and brain natriuretic peptide are abundantly expressed and secreted in the atria and ventricles, respectively. They induce diuretic/natriuretic effects, vasodilation, and counteract the actions of angiotensin II by inhibiting aldosterone secretion. The identification of natriuretic peptides has spurred a growing research field dedicated to characterizing their physiological roles in cardiovascular homeostasis and disease. Furthermore, their potential as biomarkers and therapeutic agents is under active investigation. Carperitide and sacubitril/valsartan are effective HF treatments that utilize the physiological effects of natriuretic peptides. Understanding the roles of the different members within the natriuretic peptide family in maintaining cardiovascular homeostasis, along with recognizing their pathophysiological implications in the development and progression of HF, forms the fundamental basis for the clinical significance of natriuretic peptides in the development of diagnostic and therapeutic agents for HF.