In industrialized countries, heart failure continues to be the leading cause of mortality, disability, and significant economic burden. Studies in physiology, pharmacology, and medicine have shown that activation of the RAS is a significant modulator of the development of heart failure. The ACE2-Ang-(1–7)-MasR axis plays a crucial counter-regulatory role in preventing heart failure with preserved ejection fraction due to an active RAS via the ACE-Ang-II-AT1R axis. A homolog of ACE, ACE2, is a monocarboxypeptidase that breaks down several vasoactive peptides, including the vasoconstrictive/proliferative peptide Ang-II, into Ang-(1–7). The Mas receptor mediates the vasodilatory and anti-proliferative effects of Ang (1–7). Cardiomyocytes, cardiofibroblasts, and coronary endothelial cells all have high levels of ACE2 expression. Increased ACE2 levels prevent and reverse the heart failure phenotype, even if ACE2 loss increases adverse remodeling and vulnerability to heart failure. A significant preventive mechanism against heart failure with reduced and preserved ejection fraction has been identified as involving ACE2 and Ang (1–7). In phase I and phase II clinical studies, rhACE2 was tested without causing any negative side effects while decreasing and raising plasma Ang-II and Ang-(1–7) levels, respectively. This prevented myocardial hypertrophy, fibrosis, inflammation, and diastolic dysfunction in HF patients. The control of ACE2 at the transcriptional and post-transcriptional levels, as well as the role of the ACE2-Ang-(1–7)- MasR axis in cardiac physiology and the pathogenesis of heart failure, are covered in this review. Enhancing ACE2/Ang-(1–7) action as a novel therapy for the treatment of cardiovascular disorders, such as hypertension and heart failure, is highlighted for its therapeutic and pharmacological potential.