In 2000 a novel ACE-like enzyme, eventually named ACE2, was discovered. It showed a different substrate selectively, and in particular it could not activate angiotensin I. At the same time, it was not a target of classical ACE inhibitors. Investigations were therefore started, aiming at determining the role of ACE2, and the general hypothesis that ACE2 may counteract several physiological consequences of ACE activation was introduced. In 2003 ACE2 was also identified as the initial cellular target of the SARS-CoV virus, since its spike glycoprotein was found to be a high affinity ligand of membrane ACE2. Similar properties are shared by SARS-CoV-2 virus, and the huge impact of the recent COVID-19 pandemic has triggered novel interest in ACE2, particularly in the regulation of its expression in different cell types.