The devastating clinical, psychological, and economic impact of the COVID-9 pandemic, caused by global spread of the second Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), engendered a massive response from the scientific community to rapidly understand the biology of SARS-CoV-2 and to develop interventions to prevent infection or progression to life-threatening disease. Angiotensin converting enzyme-2 (ACE2) and its interaction with the SARS-CoV-2 Spike glycoprotein, which mediates fusion of the virion envelope with the target cell membrane, emerged as a major pharmacological target, as disruption of Spike-ACE2 interaction prevents cells from becoming infected and hence from producing viral progeny. Moreover, the dysregulation of ACE2 that occurs in the context of SARS-CoV-2 infection may have broader implications for COVID-19 pathogenesis. Here we summarize the role of ACE2 as a physiologic regulator of human health, as a facilitator of SARS-CoV-2 infection, as a factor in COVID-19 disease, and as a target for pharmacological interventions.