The interferon-stimulated gene, 15 kDa (ISG15) is an interferon regulated gene that is induced as a primary response to diverse microbial and cell stress stimuli, and encodes the founding member of the ubiquitin-like protein family. ISG15 shares several common properties with other ubiquitin-like molecules (UBLs), but its activity is tightly regulated by specific signaling pathways that have a role in innate immunity.