Interferon\|stimulated gene 15 　encoded protein (ISG15) was identified as one of the first ubiquitin\|like modifier that induced by interferons. Numerous ISG15\|target proteins have been identified in tumors and virus\|infected cells. Multiple lines of evidence suggest that ISG15 plays important roles in the innate immune pathways and in cancer development. We focus on the structure and biochemical features of ISG15, as well as the mechanisms of the ISGylation of target proteins assisted with ISG15 modifier enzymes. The anti\|viral and anti\|cancer activities of ISG15 and its modifier enzymes are also discussed.