Immunotherapy of cancer has always represented a very attractive fourth-modality therapeutic approach. Over the past few years, advances in the identification of tumor antigens have opened new perspectives and provided new opportunities for a more accurate immunotherapy of cancer. However, when applied to patients with established tumors, it rarely leads to an objective response. This is in part due to the fact that tumors evade host immunity at both the induction and effector phases. In this regard, several different functional defects in T-lymphocytes that infiltrate cancers have been reported. Indeed, lymphocytes of patients with advanced malignancies are hyporeactive and functionally compromised. Furthermore, it has become clear that immunotherapeutic and gene therapeutic approaches aimed at the induction of anti-tumor cytotoxic responses should consider the resistance of tumor cells to cytotoxic mechanisms. Thus, understanding of tumor escape mechanisms may be the key to a successful immunotherapy for cancer. How tumors escape immunological destruction following the acquisition of resistance to cell death and the potential role the tumor suppressor p53 protein in immunosensitization of tumor cells will be discussed.