Resistance to flavivirus-induced disease in mice was first discovered in the 1920s and was subsequently shown to be controlled by the resistant allele of a single dominant autosomal gene. While the majority of current laboratory mouse stains have a homozygous-susceptible phenotype, the resistant allele has been found to segregate in wild mouse populations in many different parts of the world. Resistance is flavivirus specific and extends to both mosquito- and tick-borne flaviviruses. Resistant animals are infected productively by flaviviruses but produce lower virus titers, especially in their brains, as compared to susceptible mice. Decreased virus production is observed in resistant animals even during a lethal infection and the times of disease onset and death are also delayed as compared to susceptible mice. An intact immune response is required to clear flaviviruses from resistant mice. The resistant phenotype is expressed constitutively and does not require interferon induction. The Flv gene was discovered using a positional cloning approach and identified as Oas1b. Susceptible mice produce a truncated Oas1b protein. A C820T transition in the fourth exon of the gene introduced a premature stop codon and was found in all susceptible mouse strains tested. Possible mechanisms by which the product of the resistant allele could confer the resistant phenotype are discussed.