Importantly, our work suggests that stronger ISG15‐USP18 binding (reliant on the ISG15 C‐terminal tail) is required for USP18‐dependent regulation of the type I IFN response as the level of binding to USP18 reflected the level of IFN‐α signalling regulation and the permissiveness of cells to viral infection. The gene discussed is ISG15; the disease is viral infectious disease.