Ral-interacting protein (RLIP76) (RALBP1) is an anti-apoptotic non-ABC glutathione (GSH)-conjugate transporter involved in receptor-ligand endocytosis, as well as in multispecific drug transport and resistance. Partial inhibition of RLIP76 using antibodies in the absence of chemotherapy drug causes apoptosis in multiple small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) cell lines and in the presence of doxorubicin (DOX), marked synergy is observed. These findings indicated that RLIP76 should be a good target for cancer cell killing; its down-regulation would promote apoptosis through both drug-dependent and drug-independent effects. To examine the effect of complete and specific RLIP76 depletion on apoptosis, we tested the effects of RLIP76 siRNA in a number of lung cancer cell lines. Growth inhibition and apoptosis was observed in all cases upon RLIP76 depletion. Consistent with these findings, augmenting cellular RLIP76 through transfection or liposomal protein delivery conferred resistance to apoptosis mediated by either DOX or 4-hydroxynonenal (4-HNE). Taken together, our results show that RLIP76 is rational and promising new target for lung cancer therapy.