AbstractEmerging variants of SARS‐CoV‐2 and potential novel epidemic coronaviruses underline the importance of investigating various viral proteins as potential drug targets. The papain‐like protease of coronaviruses has been less explored than other viral proteins; however, its substantive role in viral replication and impact on the host immune response make it a suitable target to study. This review article focuses on the structure and function of the papain‐like protease (PLpro) of SARS‐CoV‐2, including variants of concern, and compares it to those of other coronaviruses, such as SARS‐CoV‐1 and MERS‐CoV. The protease's recognition motif is mirrored in ubiquitin and ISG15, which are involved in the antiviral immune response. Inhibitors, including GRL0617 derivatives, and their prospects as potential future antiviral agents are also discussed.