The interferon-sensitive gene 20 (ISG20) is a broad viral inhibitor previously thought to directly degrade invading viral RNA thanks to its RNase activity. This mechanism remained however controversial. In a recently published study, we have instead determined that ISG20 inhibits viral replication by impairing translation from viral RNAs and not by degrading them. Importantly, we also show that ISG20-mediated translation inhibition is distinct from previously known translation blocks (PKR, IFITs) and that ISG20 discriminates between mRNAs derived from chromosomal genes (self) and those originated from foreign genetic elements, be them viruses with a purely cytoplasmic life cycle or plasmid DNAs transcribed in the nucleus. Using orthogonal approaches, we want to identify the mechanism/s and specificities of ISG20 inhibition. In light of the current context, the characterization of the mechanism of translation inhibition by ISG20 will first focus on two RNA viruses: VSV as a model of negative-strand RNA viruses and SARS-CoV2 as a model for positive-strand RNA virus. The former will be used to decorticate and zoom into the mechanism of viral specificity and action of ISG20 in BSL2 conditions and the latter will be used to more finely characterize the specificity or differences with respect to viruses of high relevance for human health. After, the results obtained here will be extended to other viral pathogens as Zika or Retroviruses. By studying a mechanism that broadly affects viral replication, we aim at characterizing a vulnerable step common to different viruses.