In random chemical mutagenesis, gene discovery is driven by phenotypes rather than by hypotheses. A standard dose of N-ethyl-N-nitrosourea results in approximately 30 coding mutations in male G1 mice, of which approximately 4 can be propagated to homozygosity in 3 generations. In recent years, large-scale screens of such G3 mice for phenotypes of interest to immunologists have revealed clues to the number of genes responsible for key immune responses, such as innate recognition of pathogens and autoantibody production. More than 20 of the phenotypes that exhibit a simple (Mendelian) pattern of inheritance have been mapped. Novel alleles have revealed new pathways of host defense, allergy and autoimmunity.