Tumor resistance to conventional therapies is a major problem in cancer treatment. While tumors initially respond to radiation or chemotherapies, subsequent treatments with these conventional modalities are ineffective against relapsed tumors. The problem of tumor resistance to chemotherapy and radiation has led to the development of immunotherapy and gene-based therapies. These alternative therapeutic approaches are intensely explored because they are supposed to be more tumor specific and better tolerated than the conventional therapies. Recent advances in apoptosis have revealed that resistance to apoptosis is one of the major mechanisms of tumor resistance to conventional therapies. Resistance to apoptosis is a naturally acquired characteristic during oncogenesis and is selected for after successive rounds of conventional therapies. Resistance to apoptosis involves dysregulation and/or mutation of apoptotic signaling molecules that render tumor cells unresponsive to apoptotic stimuli. Since both immunotherapy and chemotherapy kill tumors by apoptosis and the killings are signaled through a central core apoptotic program, dysregulation of this central program and development of resistance to apoptosis in chemoresistant cells could render them cross-resistant to immunotherapy. Therefore, in order to establish an effective antitumor response and to complement immunotherapy and gene-based therapies, cross-resistance due to resistance to apoptosis must be overcome. In this review, based on prior findings and recent evidence, we put forth a model, verified experimentally, in which chemoresistant tumor cells can be sensitized to immune-mediated killing by subtoxic concentrations of chemotherapeutic drugs/factors. The model involves two complementary signals. The first signal is a sensitizing signal that regulates pro/antiapoptotic targets, thus facilitating the apoptotic signal. The second apoptotic signal initiates a partial activation of the apoptotic signaling pathway, and activation is completed by complementation with signal one. Thus, effective killing of immunoresistant cells is achieved by both signals. The two-signal approach provides a new strategy to overcome cancer cross-resistance to immunotherapy and opens new avenues for the development of more effective and selective immunosensitizing agents.