Most anti-cancer therapies induce apoptotic cell death, but a major barrier to long-term cancer treatments is the generation of apoptosis-resistant tumor cells. Tumor cells that become resistant to one therapy are usually cross-resistant to subsequent therapies, including those with different cellular/molecular targets, suggesting that resistant tumor cells acquire modifications of the general apoptotic pathway. Most solid tumors are characterized by infiltration of lymphocytes (tumor infiltrating lymphocytes, TIL), which may serve as a basis for new strategies to generate tumor specific lymphocytes. However, TIL frequently are unable to kill autologous tumor cells suggesting that they are anergic/tolerant. It is possible that the TIL are functional but the tumor cells are resistant to TIL-mediated apoptotic pathways. Previous findings revealed that resistant tumor cells can be sensitized with cytokines or subtoxic concentrations of chemotherapeutic drugs and restore killing by cytotoxic lymphocytes. In this study, we examined whether TIL can kill autologous and allogeneic tumor cells following sensitization with chemotherapeutic drugs. Renal and prostate cancer-derived TIL were cytotoxic to chemosensitized resistant tumor cells. Killing by TIL was found to be perforin-dependent and perforin-independent. These findings demonstrate that combination drug and immunotherapy may be able to overcome tumor cell resistance to killing by TIL. Further, in vivo sensitization of drug-resistant tumor cells by subtoxic doses of sensitizing chemotherapeutic drugs may result in tumor regression by the host immune system.