The primary reason for the failure to cure patients with cancer remains the development of multiple mechanisms of resistance to cytotoxic agents. The two major effectors of tumor cell killing include genotoxic agents and cell-mediated immunity. Genotoxic agents function primarily by initiating pathways leading to apoptosis or programmed cell death, whereas immune-mediate cytotoxicity utilizes both programmed cell death-promoting as well as cytolytic processes. The mechanisms leading to treatment resistance initially involve alterations in the way tumor cells transport, metabolize, and provide substrates for cytotoxic agents. Beyond these specific mechanisms, tumor cells may also express alterations in the regulators and effectors of apoptotic death, thus creating a more generalized resistance pattern. Through a variety of other mechanisms, tumor cells may also decrease specific antigen expression or the ability to costimulate T lymphocytes. The result of antigen recognition in the absence of costimulation can lead to antigen-specific tolerance, which may also represent a major form of escape from immune-mediated killing. The elucidation of these mechanisms of resistance to therapy and tumor cell survival should form the basis for the development of more effective therapies.