The renin-angiotensin system (RAS) is a critical regulatory mechanism for cardiovascular homeostasis. The classical arm of the RAS involves renin and angiotensin-converting enzyme (ACE), generating angiotensin II (Ang II) from angiotensinogen. Ang II acts on its AT1 receptor to increase blood pressure, retain salt and water, and induce cardiovascular hypertrophy and fibrosis. However, Ang II can also activate the AT2 receptor (AT2R), which has opposing effects to the AT1 receptor. Additionally, ACE2 cleaves Ang II to form angiotensin-(1-7) (Ang-(1-7)), which interacts with the Mas receptor. Ang-(1-7) has anti-proliferative, anti-fibrotic, and anti-inflammatory effects, and its levels are altered in various diseases. The discovery of the alternative arm of the RAS, including AT2R, ACE2, and Ang-(1-7), has expanded our understanding of RAS function in health and disease. Therapeutic interventions targeting these components, such as activating ACE2, increasing Ang-(1-7) production, or modulating AT2R, offer new opportunities for treating a range of cardiovascular and metabolic disorders. Clinical trials are underway to evaluate these novel therapies.The renin-angiotensin system (RAS) is a critical regulatory mechanism for cardiovascular homeostasis. The classical arm of the RAS involves renin and angiotensin-converting enzyme (ACE), generating angiotensin II (Ang II) from angiotensinogen. Ang II acts on its AT1 receptor to increase blood pressure, retain salt and water, and induce cardiovascular hypertrophy and fibrosis. However, Ang II can also activate the AT2 receptor (AT2R), which has opposing effects to the AT1 receptor. Additionally, ACE2 cleaves Ang II to form angiotensin-(1-7) (Ang-(1-7)), which interacts with the Mas receptor. Ang-(1-7) has anti-proliferative, anti-fibrotic, and anti-inflammatory effects, and its levels are altered in various diseases. The discovery of the alternative arm of the RAS, including AT2R, ACE2, and Ang-(1-7), has expanded our understanding of RAS function in health and disease. Therapeutic interventions targeting these components, such as activating ACE2, increasing Ang-(1-7) production, or modulating AT2R, offer new opportunities for treating a range of cardiovascular and metabolic disorders. Clinical trials are underway to evaluate these novel therapies.