To elucidate the mechanisms involved in adaptation of lung epithelial cells to cadmium (Cd), we established a cell line that exhibits Cd-resistance (RWI38). RWI38 showed ~5-fold greater Cd-resistance (MTT assays) than WI38 cells, and cross-resistance to Zn and cisplatin. RWI38 cells also demonstrated an upregulated level of multidrug resistance-associated protein (MRP) and metallothionein (MT) (as shown by Western blot analysis and RT-PCR studies). The protein level of MRP decreased after Cd exposure in WI38 cells, but was sustained at high levels in RWI38 cells, leading led to enhanced calcein efflux. Cd induced Akt phosphorylation in RWI38 but not WI38 cells; this was prevented by probenecid or siRNA for MRP, both of which led to enhanced cell death, as demonstrated by capsase-3 activation and decreased cell viability. These results suggest a functional role for MRP in the regulation of the Akt pathway as well in the efflux pumping of drugs, thereby contributing toward the adaptation of cells to Cd toxicity. The findings of this study could be potentially beneficial in the design of therapeutic targets for Cd-induced tumor progression.