The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been attributed to providing regulatory signals required for the priming of major histocompatibility complex class I-restricted CD8+ cytolytic T lymphocytes, which are thought to mediate tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) indicates a broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils and macrophages, which produce superoxide and nitric oxide, respectively. These cells then collaborate within the site of tumor challenge to cause its destruction. The study demonstrates that effective antitumor immunity is critically dependent on CD4+ T cells, which orchestrate multiple immunologic effector arms, dependent on both Th1 and Th2 cytokines.The induction of optimal systemic antitumor immunity involves the priming of both CD4+ and CD8+ T cells specific for tumor-associated antigens. The role of CD4+ T helper cells (Th) in this response has been attributed to providing regulatory signals required for the priming of major histocompatibility complex class I-restricted CD8+ cytolytic T lymphocytes, which are thought to mediate tumor killing. However, analysis of the effector phase of tumor rejection induced by vaccination with irradiated tumor cells transduced to secrete granulocyte/macrophage colony-stimulating factor (GM-CSF) indicates a broader role for CD4+ T cells in orchestrating the host response to tumor. This form of immunization leads to the simultaneous induction of Th1 and Th2 responses, both of which are required for maximal systemic antitumor immunity. Cytokines produced by these CD4+ T cells activate eosinophils and macrophages, which produce superoxide and nitric oxide, respectively. These cells then collaborate within the site of tumor challenge to cause its destruction. The study demonstrates that effective antitumor immunity is critically dependent on CD4+ T cells, which orchestrate multiple immunologic effector arms, dependent on both Th1 and Th2 cytokines.