Immune responses to tumor-associated antigens exist in tumor-bearing hosts but are usually not successful in eliminating malignant cells or preventing the development of metastases. Patients with cancer generate robust immune responses to infectious agents (bacteria and viruses) perceived as a “danger signal” but only ineffective, weak responses to tumor-associated antigens, which are considered as “self.” This fundamental difference in responses to self versus non-self is further magnified by the ability of tumors to subvert the host immune system. Tumors induce dysfunction, as well as apoptosis in CD8⁺ antitumor effector cells. The escape of tumors from immune cells is mediated by several distinct molecular mechanisms. Insights into these mechanisms and more effective control of tumor-orchestrated immune dysfunction are needed. Novel strategies for immunotherapy of cancer must address protection and survival of antitumor effector cells in the tumor microenvironment. (J Allergy Clin Immunol 2003;111:S677-86.)