Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is at present an emerging global public health crisis.Angiotensin converting enzyme 2 (ACE2) and trans-membrane protease serine 2 (TMPRSS2) are the two major host factors that contributeto the virulence of SARS-CoV-2 and pathogenesis of coronavirus disease-19 (COVID-19). Transmission of SARS-CoV-2 from animal tohuman is considered a rare event that necessarily requires strong evolutionary adaptations. Till date no other human cellular receptors areidentified beside ACE2 for SARS-CoV-2 entry inside the human cell. Proteolytic cleavage of viral spike (S)-protein and ACE2 byTMPRSS2 began the entire host–pathogen interaction initiated with the physical binding of ACE2 to S-protein. SARS-CoV-2 S-proteinbinds to ACE2 with much higher affinity and stability than that of SARS-CoVs. Molecular interactions between ACE2-S and TMPRSS2-Sare crucial and preciously mediated by specific residues. Structural stability, binding affinity and level of expression of these threeinteracting proteins are key susceptibility factors for COVID-19. Specific protein–protein interactions (PPI) are being identified thatexplains uniqueness of SARS-CoV-2 infection. Amino acid substitutions due to naturally occurring genetic polymorphisms potentially alterthese PPIs and poses further clinical heterogeneity of COVID-19. Repurposing of several phytochemicals and approved drugs againstACE2, TMPRSS2 and S-protein have been proposed that could inhibit PPI between them. We have also identified some novel leadphytochemicals present in Azadirachta indica and Aloe barbadensis which could be utilized for further in vitro and in vivo anti-COVID-19drug discovery. Uncovering details of ACE2-S and TMPRSS2-S interactions would further contribute to future research on COVID-19.