A clonal cell line, R40F, was selected from a heterogenous population of Cd 2+ and Zn 2+-resistant CHO-K1 cells. These R40F cells demonstrated resistance to 120- and 4-fold higher concentrations of Cd 2+ and Zn 2+, respectively, than did wild type CHO-K1 cells. When cultured in the presence of low concentrations of Cd 2+ (0.5–1.0 μM), the accumulation of intracellular Cd 2+ in R40F cells appears to be significantly less than in wild type cells. Since R40F cells maintained in medium containing high concentrations of Cd 2+ (200 μM) retain levels of Cd 2+ equivalent to the intracellular concentration observed in wild type cells exhibiting cytotoxicity, it is assumed that reduced Cd 2+ transport alone is unlikely to account for the resistance to Cd 2+ toxicity. Exposure of R40F cells to non-toxic (2 μM or 100 μM) or toxic (200 μM) Zn 2+ levels resulted in an accumulation of Zn 2+ equal to, or greater than, that observed in the wild type cell. When compared to the basal level in uninduced wild type cells, metallothionein levels were elevated 14- and 23-fold, respectively, in R40F cells cultured in the presence of 0.5 μM Cd 2+ and 100 μM Zn 2+. These results are consistent with the hypothesis that R40F cells express Cd 2+ and Zn 2+ resistance as a consequence of a reduction in unbound intracellular Cd 2+ levels and an elevation of metallothionein synthesis.