A single germ line gene mutation at a tumor susceptibility locus in a rodent model of hereditary human renal cancer caused a 70-fold increase in susceptibility to chemical carcinogenesis. A carcinogen that targeted both renal epithelial and mesenchymal cells caused an increase in tumors of epithelial origin in susceptible animals; the number of carcinogen-induced mesenchymal tumors was unaffected by the presence of the mutation at the susceptibility locus. Thus, this mutation defines a genetic locus for susceptibility to carcinogen-induced tumors and modulation of carcinogen susceptibility by this locus exhibits cell-type specificity.