The polybasic furin cleavage site insertion with four amino acid motifs (PRRA) in spike protein's S1/S2 junction site is important in determining viral infectivity, transmission, and host range. However, there is no review so far explaining the effect of the furin cleavage site of the spike protein on SARS‐CoV‐2 replication and pathogenesis in the host and immune responses and vaccination. Therefore, here we specifically focused on genomic evolution and properties of the cleavage site of spike protein in the context of SARS‐CoV‐2 followed by its effect on viral entry, replication, and pathogenesis. We also explored whether the spike protein furin cleavage site affected the host immune responses and SARS‐CoV‐2 vaccination. This review will help to provide novel insights into the effects of polybasic furin cleavage site on the current COVID‐19 pandemic. Highlights The genomic evolution and properties of the cleavage site of spike protein in the context of SARS‐CoV‐2 are discussed. The effects of furin cleavage site of spike protein on viral entry, replication, and pathogenesis are reviewed. Whether the host immune responses and SARS‐CoV‐2 vaccination are affected by the spike protein furin cleavage site was also discussed.