Over the past few years, several groups have identified new genes that are transcriptionally induced downstream of type I interferon (IFN) signalling and that inhibit infection by individual or multiple families of viruses. Among these IFN-stimulated genes with antiviral activity are two genetically and functionally distinct families — the IFN-induced protein with tetratricopeptide repeats (IFIT) family and the IFN-induced transmembrane protein (IFITM) family. This Review focuses on recent advances in identifying the unique mechanisms of action of IFIT and IFITM proteins, which explain their broad-spectrum activity against the replication, spread and pathogenesis of a range of human viruses.