Although the relevance of ubiquitin has been already defined in different processes linked to genome stability, such as DNA replication and DNA damage response, the role of other ubiquitin-like modifiers is still elusive. One of these modifiers is the Interferon Stimulated Gene 15, ISG15, which is strongly induced during pathogen infection via interferon type-1, being part of the innate immunity. Interestingly, ISG15 and its conjugation – a process called ISGylation – are also induced by different genotoxic treatments, such as camptotechin (CPT), hydroxyurea (HU) and UV light. Recently reported to be deregulated in most human malignancies, ISG15 is emerging as an important oncoprotein and a potential diagnostic and therapeutic target for cancer. Even though many proteomic studies identified different proteins involved in DNA repair and DNA replication as potential targets of ISG15, a functional and comprehensive analysis of these factors is still missing. We aim at further expanding these studies, by investigating the role of ISG15 – both as free molecule or conjugated to targets – in the maintenance of genome integrity, by focusing on their specific role in the DNA damage response and DNA replication.