The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) virus genome encodes 4 major structural proteins: the spike (S) protein; the nucleocapsid (N) protein; the membrane (M) protein; and the envelope (E) protein. The S protein is responsible for facilitating entry of the CoV into the target cell. The routes employed by SARS-CoV include endocytosis and membrane fusion. The route employed by SARS-CoV-2 is via endocytosis; whether SARS-CoV-2 enters cells by membrane fusion is not known. Binding of the S protein of SARS-CoV to angiotensin-converting enzyme 2 (ACE2) leads to the uptake of the virions into endosomes, where the viral S protein is activated by the pH-dependent cysteine protease cathepsin L. Activation of the S protein by cathepsin L can be blocked by bafilomycin A1 and ammonium chloride, which indirectly inhibit the activity of cathepsin L by interfering with endosomal acidification. Chloroquine and hydroxychloroquine are weak bases that diffuse into acidic cytoplasmic vesicles such as endosomes, lysosomes, or Golgi vesicles and thereby increases their pH. MDL28170 inhibits calpain and cathepsin L. SARS-CoV can also directly fuse with host cell membranes, after processing of the virus spike protein by transmembrane protease serine 2 (TMPRSS2), a type II cell membrane serine protease. Camostat mesylate is an orally active serine protease inhibitor. Modified from Simmons et al. (25).