Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) is a novel member of the Coronaviridae family that is the causative agent of coronavirus disease- 19 (COVID-19), which is now pandemic in the world. Various proteins characteristically responsible for pathogenesis are categorized as structural proteins (S, M, E, and N), non-structural proteins, and accessory proteins (ORF3a, ORF6, ORF7a, ORF7b, ORF8, and ORF10). Substitution of 380 amino acids and mutations in SARSCoV- 2 compared to other SARS-like coronaviruses characteristically plays a key role in entering the development of infection. S1/S2 of S protein has a specific differential role in SARS-CoV-2 stabilization and resultant infection. In addition to these key proteins, the host and virus-related proteins play risk factors in the spread of this disease. The current chapter will describe the structure of key proteins, their role in pathogenesis, starting from viral attachment leading to the infection in the host compared to the viruses belonging to Betacoronaviruses.