Mouse susceptibility to experimental infections with flaviviruses is significantly influenced by a cluster of genes on chromosome 5 encoding a family of proteins with enzymatic properties, the 2′–5′ oligoadenylate synthetases (OAS). Positional cloning of the locus in question has revealed that susceptibility of laboratory inbred strains to this class of virus is associated with a nonsense mutation in the gene encoding the OAS1B isoform. Analysis of the molecular structure of the cluster in different mammalian species including human indicates that the cluster is extremely polymorphic with a highly variable number of genes and pseudogenes whose functions are not yet completely established. Although still preliminary, a few recent observations also substantiate a possible role for OAS1 in human susceptibility to viral infections (West Nile virus, SARS, etc.) and its possible involvement in some other diseases such as type 1 diabetes and multiple sclerosis. Finally, convergent observations indicate that the molecules encoded by the 2′–5′ OAS cluster might be involved in other fundamental cellular functions such as cell growth and differentiation, gene regulation, and apoptosis.