The world is facing an unprecedented crisis due to “COVID-19” pandemic and the number of cases are constantly soaring. ACE2 is ubiquitously present in different organs including nasal epithelium, conducting airways and alveolar epithelium. It is found that S-protein of SARS-CoV-2 activated by TMPRSS2 targets ACE2 for gaining entry into host cells. Eventually the downregulation of ACE-2 occurs, either directly because of viral binding and endocytosis or indirectly because of cell lysis or ADAM17 activity. This results in homeostatic disruption of ACE/ACE2 system balance and the activity of activator pathways of Renin-Angiotensin-Aldosterone-System (ACE/angiotensin II/AT1R pathway) remains uninhibited by inhibitor pathways (angiotensin-(1-7)/ACE-2/MasR pathway). This will flare up immune response, destroy the alveolar type II pneumocyte and release pro inflammatory cytokines such as IL-6, TNF, etc. As a result “COVID-19” manifests as different symptoms of ranging from mild flu like to severe ARDS. This review highlights further prospect of studies on ACE2 or S-protein as a therapeutic agent or target.