During viral infections ISG15 can restrict infection by direct modification of viral proteins (Zhao et al., 2010), by modification of host proteins that are important to viral replication (Pincetic et al., 2010), by non-specific modification of newly translated proteins to target viral capsid (Durfee et al., 2010) and finally in the context of infection in vivo it can have non-conjugation dependent roles either within the cell or as a cytokine when secreted from polymorphonuclear leukocytes (D'Cunha et al., 1996; Werneke et al., 2011; Bogunovic et al., 2012). Here, ISG15 is linked to infection.