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The coronavirus disease 2019(COVID-19)outbreak is caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2).Angiotensin-converting enzyme 2(ACE2)was rapidly identified as the critical functional receptor for SARS-CoV-2.ACE2 is well-known as a counter-regulator of the renin-angiotensin system(RAS)and plays a key role in the cardiovascular system.Given that ACE2 func-tions as both a SARS-CoV-2 receptor and a RAS modulator,the treatment for COVID-19 presents a dilemma of how to limit virus entry but protect ACE2 physiological functions.Thus,an in-depth sum-mary of the recent progress of ACE2 research and its relationship to the virus is urgently needed to pro-vide possible solution to the dilemma.Here,we summarize the complexity and interplay between the coronavirus,ACE2 and RAS(including anti-RAS drugs).We propose five novel working modes for func-tional receptor for SARS-CoV-2 infection and the routes of ACE2-mediated virus entering host cells,as well as its regulatory mechanism.For the controversy of anti-RAS drugs application,we also give theo-retical analysis and discussed for drug application.These will contribute to a deeper understanding of the complex mechanisms of underlying the relationship between the virus and ACE2,and provide guidance for virus intervention strategies.