Proposed model of SARS-CoV-2 entry into the host cells. Based on available literature on SARS-CoV and recent findings on SARS-CoV-2, we suggest two different mechanisms that can be employed by SARS-CoV-2 to enter into the ACE2 expressing cells. (1) Initially the virus may use the cell membrane mode of entry. The first step is the binding of the spike protein of the virus with ACE2 receptors expressed on the plasma membrane of host cells. (2) The attachment with ACE2 is followed by the cleavage of S protein by membrane bound proteases like TMPRSS2. TMPRSS2 cleaves the membrane bound virus at both S1/S2 boundary as well as at S2’ site. (3) This activates the fusion machinery, and subsequently, the viral membrane fuses with the host cell plasma membrane. (4) This leads to release of the viral nucleocapsid into the cytoplasm. (5) The replication, assembly, and maturation of virus takes places in the cytoplasm. (6) Before dissemination, SARS-CoV-2 may also undergo pre-activation in the golgi apparatus by furin proteases. (7) The fully mature and pre-activated SARS-CoV-2 eventually disseminates from host cells by exocytosis. During subsequent infection cycles, the virus may utilize either cell membrane or (8–11) the more probable endocytic entry route. In the endocytic mode of entry, (8) after attachment with ACE2, (9) the virus gets endocytosed and (10) then processed at the S2’ region by endosomal proteases like cathepsins, to activate membrane fusion. (11) Finally, the viral components are released into the cytoplasm by fusion of the viral membranes with endosomal membrane, leading to repeat of the cycle.