Although life span is generally considered to be under polygenic control, we obtained experimental evidence of Mendelian genes exerting major effects on life span differences between two inbred strains of Drosophila melanogaster. Our data indicate two loci with major effects, one being autosomal and the other sex-linked. The alleles at the autosomal locus are designated A1 and A2, the latter producing longer life. Heterozygotes, A1A2, exhibit over-dominance. The alleles at the sex-linked locus, designated X1 and X2, produce life-extending effects. X1 revealed a dosage effect, causing homozygous females to live longer than hemizygous males; X2 showed no dosage effect. The identified genes are considered to control the period of activity of many genes maintaining life.