Metastatic disease is the principle cause of death for most patients with breast cancer. Conventional therapies including radiation therapy and chemotherapy are largely uneffective against metastatic disease. It is now generally appreciated that the immune system can destroy tumor cells, and numerous novel immunotherapies are currently under development. Many of these immunotherapies are dependent on activation of the host's immune system so the success of a cancer vaccine will depend on the immune status of the patient. Tolerance to tumor antigens, tumor-induced immune suppression, and the presence of immunomodulatory genes that block the development of tumor-specific immunity can potentially interfere with the therapeutic efficacy of immune-based therapies. Studies from the authors' laboratory demonstrate that although mice with bulky primary mammary tumors are immunosuppressed for T cell and antibody-mediated immunity, surgical removal of the primary tumor reverses the suppression, even when disseminated metastatic disease is present. The post-surgical reversal is associated with a large decrease in myeloid suppressor cells. In addition to tumor-induced suppression, two genes, the Stat6 and CD1 genes, are also associated with inhibiting tumor-specific immunity, since mice deficient for these genes have dramatically enhanced resistance to metastatic mammary carcinoma. Therefore, optimal delivery of immunotherapy should be coordinated with methodology that decreases immune suppression and eliminates or blocks inhibitory factors.