ACE2 (angiotensin-converting enzyme 2) is a multifunctional protein with critical roles in the renin-angiotensin system (RAS), amino acid transport, and as a receptor for SARS-CoV and SARS-CoV-2. It is widely expressed in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 is the receptor for SARS-CoV-2, the virus causing COVID-19, and plays a key role in regulating the RAS. The binding of SARS-CoV-2 to ACE2 leads to its internalization and proteolytic cleavage, which may contribute to the pathogenicity of the virus. ACE2 also has protective roles in cardiovascular and lung diseases, including heart failure, hypertension, and lung fibrosis. The ACE2 system is a critical protective pathway against these conditions, and recombinant ACE2, gene delivery, and Ang 1–7 analogs have shown potential as therapies. The loss of ACE2 function is associated with increased inflammation, fibrosis, and vascular permeability. ACE2 is also involved in gut dysbiosis and the gut-lung axis, which may contribute to the progression of COVID-19. The ACE2/Ang 1–7/MasR axis has emerged as a key regulatory pathway in the RAS, with ACE2 acting as a negative regulator. ACE2 deficiency is linked to increased susceptibility to cardiovascular and lung diseases, while increased ACE2 activity has protective effects. The role of ACE2 in diabetes and its impact on the RAS is also significant, with ACE2 deficiency exacerbating diabetic complications. The ACE2 receptor is also involved in the pathogenesis of SARS-CoV-2, with the virus utilizing ACE2 for entry into host cells. The interaction between ACE2 and the SARS-CoV-2 spike protein is critical for viral entry, and the loss of ACE2 function may contribute to the severity of the disease. ACE2 is also involved in the regulation of inflammatory responses and the balance between protective and proinflammatory pathways in the RAS. The ACE2/Ang 1–7/MasR axis is a key target for therapeutic interventions in cardiovascular and lung diseases, including COVID-19. The development of therapies targeting ACE2, such as recombinant ACE2 and Ang 1–7 analogs, is an important area of research. The role of ACE2 in the RAS and its implications for the pandemic and associated cardiovascular diseases are highlighted in this review.ACE2 (angiotensin-converting enzyme 2) is a multifunctional protein with critical roles in the renin-angiotensin system (RAS), amino acid transport, and as a receptor for SARS-CoV and SARS-CoV-2. It is widely expressed in the lungs, cardiovascular system, gut, kidneys, central nervous system, and adipose tissue. ACE2 is the receptor for SARS-CoV-2, the virus causing COVID-19, and plays a key role in regulating the RAS. The binding of SARS-CoV-2 to ACE2 leads to its internalization and proteolytic cleavage, which may contribute to the pathogenicity of the virus. ACE2 also has protective roles in cardiovascular and lung diseases, including heart failure, hypertension, and lung fibrosis. The ACE2 system is a critical protective pathway against these conditions, and recombinant ACE2, gene delivery, and Ang 1–7 analogs have shown potential as therapies. The loss of ACE2 function is associated with increased inflammation, fibrosis, and vascular permeability. ACE2 is also involved in gut dysbiosis and the gut-lung axis, which may contribute to the progression of COVID-19. The ACE2/Ang 1–7/MasR axis has emerged as a key regulatory pathway in the RAS, with ACE2 acting as a negative regulator. ACE2 deficiency is linked to increased susceptibility to cardiovascular and lung diseases, while increased ACE2 activity has protective effects. The role of ACE2 in diabetes and its impact on the RAS is also significant, with ACE2 deficiency exacerbating diabetic complications. The ACE2 receptor is also involved in the pathogenesis of SARS-CoV-2, with the virus utilizing ACE2 for entry into host cells. The interaction between ACE2 and the SARS-CoV-2 spike protein is critical for viral entry, and the loss of ACE2 function may contribute to the severity of the disease. ACE2 is also involved in the regulation of inflammatory responses and the balance between protective and proinflammatory pathways in the RAS. The ACE2/Ang 1–7/MasR axis is a key target for therapeutic interventions in cardiovascular and lung diseases, including COVID-19. The development of therapies targeting ACE2, such as recombinant ACE2 and Ang 1–7 analogs, is an important area of research. The role of ACE2 in the RAS and its implications for the pandemic and associated cardiovascular diseases are highlighted in this review.