Genetic analysis in mice and other mammals showed that the interferon (IFN) system is important for resistance to viral and bacterial infections. IFN is thought to play a similar role in non-mammalian species, although knowledge is lagging behind. Molecular cloning revealed low but significant conservation of IFN genes in birds and fish. Whereas chickens and other birds have multiple genes for IFN-alpha and single genes for IFN-beta and IFN-gamma like most mammals, fish appear to have fewer IFN genes. Nonetheless, regulation of IFN-alpha and IFN-beta genes in response to viral and non-viral activators is well conserved in birds and fish, and similar sets of genes are induced in response to IFN in mammalian and non-mammalian vertebrates. IFN-like activities were also observed in reptiles and amphibians, but genes encoding these activities have not yet been cloned. Insights into the IFN system of non-mammalian species may lead to improved prophylactic and therapeutic approaches against virus infections in poultry and fish.