The post-translational modification of substrates with ubiquitin and ubiquitin-like proteins is one of the most prevalent and complex signalling events in eukaryotic cells. As a result, many diseases are caused by mutations or mis-regulation of the proteins involved in controlling these signalling pathways. One process that is heavily reliant on these signals is the cell’s defence response against viral infection. Interferon-stimulated gene 15 (ISG15) is a ubiquitin-like protein, which is highly upregulated upon viral infection and interferon stimulation, resulting in the attachment of ISG15 to a vast array of substrates. In turn, many viruses have evolved sophisticated mechanisms to disarm this host defence system. However, a lack of available tools to study ISG15 and mechanistic information on how these signals result in specific cellular outcomes has obstructed our understanding of this ubiquitin-like protein. In my seminar, I will present our recent progress in this area and discuss key outstanding questions and future directions.