Cadmium (Cd++) is a widespread environmental pollutant and classifed as an IARC `Category I' human carcinogen. Cd++can also cause severe renal toxicity and may be involved clinically in cardiovascular disease and osteoporosis. Genetic differences in sensitivity to cadmium toxicity have been noted in humans, whereas, among inbred mouse strains, unequivocal genetic data exist. Resistance to cadmium-induced testicular damage was reported in 1973 to be associated with a single major recessive gene, namedCdm, which has now been localized to mouse chromosome (Chr) 3. Using polymorphic microsatellite markers and semiquantitative histological parameters, we have corroborated the original 1973 data concerning mendelian inheritance and have further refined the region containing theCdmgene from more than 24 cM to 0.64 cM (estimated 40–80 genes). We phenotyped 26 recombinant inbred lines generated from C57BL/6 J (B6, resistant) and DBA/2 J (D2, sensitive) inbred mice, and determined that theCdmgene maps between microsatellite markers D3Mit110 and D3Mit255. Although toxicity to numerous heavy metals is well known, virtually no molecular mechanisms have yet been uncovered either in humans or laboratory animals. Identification and characterization of the mouseCdmgene should enhance our understanding of heavy metal toxicity by identifying and characterizing, for the first time, a major mammalian gene responsible for susceptibility to diseases caused by heavy metal toxicity.