Ubiquitin-specific protease 18 (USP18), originally referred to as UBP43, with a calculated molecular weight of 43 kDa that was first discovered during the analysis of differentially expressed genes in acute myeloid leukemia 1 (AML1)-eight twenty-one (ETO) knock-in mice [31] and later in the analysis of virus-infected porcine alveolar macrophages [32] and human melanoma cell lines [33], is the major DUB that reverses ISGylation [34,35,36]. Here, USP18 is linked to melanoma.