At the beginning of the COVID-19 pandemic, there was increasing concern that therapy with renin-angiotensin-system (RAS) inhibitors, such as angiotensin-converting enzyme (ACE) inhibitors or angiotensin receptor blockers, might increase the risk of infection, severe illness, or death from COVID-19. The renin-angiotensin system (RAS) plays a significant role in the fibrogenesis and inflammatory destruction of numerous organs, including the liver and lungs, in COVID-19 patients. However, the clinical fate of these individuals is unknown. ACE2 catalyzes the conversion of angiotensin II to angiotensin-(1–7), and the ACE2/angiotensin-(1–7)/MAS axis counteracts the detrimental effects of the renin-angiotensin system (RAS), which plays a key role in maintaining physiological function. As well as the pathophysiological equilibrium of the organism. In addition to the direct viral impacts and inflammatory and immunological factors involved in the pathogenesis of COVID-19, ACE2 down regulation and an imbalance between RAS and ACE2/angiotensin-(1–7)/MAS the following infection may also contribute to multiple organ damage in COVID-19. Is. -19. The SARS-CoV-2 spike glycoprotein, which binds to ACE2, is a possible target for creating particular medicines, antibodies, and vaccines. Restoring the equilibrium between the RAS and ACE2/angiotensin-(1–7)/MAS may aid in the prevention of limb injuries. In this chapter, we’ll look at the role of ACE2 in COVID-19 and possible therapeutic targets for it to learn more about how to treat the pandemic. © 2025 Elsevier B.V., All rights reserved.