The article reviews the multifaceted roles of angiotensin-converting enzyme 2 (ACE2) in physiology and pathophysiology, highlighting its significance in the renin-angiotensin system (RAS) and its role as the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV-2). ACE2 is a key regulator of the RAS, converting angiotensin II (Ang II) into angiotensin 1–7 (Ang 1–7), which has cardioprotective effects. It is widely expressed in various tissues, including the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. The loss of ACE2 function following SARS-CoV-2 infection leads to endocytosis and proteolytic cleavage, contributing to multiorgan dysfunction and inflammation. Recombinant ACE2 (rhACE2) has shown therapeutic potential in clinical trials, reducing systemic inflammation and shifting the RAS peptide balance. The review also discusses the link between ACE2, gut dysbiosis, and cardiovascular disease, emphasizing the importance of maintaining ACE2 levels to prevent and treat conditions such as heart failure, hypertension, and diabetic complications. Additionally, it explores the role of ACE2 in lung diseases, including acute respiratory distress syndrome (ARDS) and pulmonary hypertension, and the potential of targeting the ACE2/Ang 1–7 axis for therapeutic interventions.The article reviews the multifaceted roles of angiotensin-converting enzyme 2 (ACE2) in physiology and pathophysiology, highlighting its significance in the renin-angiotensin system (RAS) and its role as the receptor for severe acute respiratory syndrome coronavirus (SARS-CoV-2). ACE2 is a key regulator of the RAS, converting angiotensin II (Ang II) into angiotensin 1–7 (Ang 1–7), which has cardioprotective effects. It is widely expressed in various tissues, including the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. The loss of ACE2 function following SARS-CoV-2 infection leads to endocytosis and proteolytic cleavage, contributing to multiorgan dysfunction and inflammation. Recombinant ACE2 (rhACE2) has shown therapeutic potential in clinical trials, reducing systemic inflammation and shifting the RAS peptide balance. The review also discusses the link between ACE2, gut dysbiosis, and cardiovascular disease, emphasizing the importance of maintaining ACE2 levels to prevent and treat conditions such as heart failure, hypertension, and diabetic complications. Additionally, it explores the role of ACE2 in lung diseases, including acute respiratory distress syndrome (ARDS) and pulmonary hypertension, and the potential of targeting the ACE2/Ang 1–7 axis for therapeutic interventions.