A closely related homolog of ubiquitin in vertebrates is the UbL polypeptide ISG15, an interferon-inducible gene product that is strongly upregulated following viral or bacterial infection [10] . However, the molecular and regulatory consequences of ISGylation remain unknown [11] . ISG15 consists of two ubiquitin domains in a tandem arrangement, similar to FAT10. Unlike other members of the UbL family, ISG15 co-opts at least one of ubiquitin's conjugating enzymes, Ubc8 [12, 13] and the ubiquitin ligase Herc5 [14] [15] [16] [17] . USP18 constitutes the only presently appreciated isopeptidase specific for ISG15, and its absence has profound effects on innate immunity, leading to increased resistance to certain viral infections [18, 19] . Notably, these effects appear not to be contingent upon proteolytic activity of USP18 [20, 21] . Apart from USP18, additional proteases for ISG15 must exist, since the ISG15 precursor protein is cleaved properly in USP18 knockout mice [19] .