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To develop new vaccines for the treatment of patients with cancer, target antigens presented on tumor cell surfaces have been cloned. Many of these antigens are non-mutated differentiation antigens and are expressed by virtually all melanomas, making them attractive components for a widely efficacious melanoma vaccine. These antigens are also expressed by melanocytes, however, and are likely to be subject to immune tolerance. A central challenge for tumor immunologists has thus been the breaking of tolerance to cancer antigens. We review recent clinical trials using experimental cancer vaccines, including recent evidence that therapeutic vaccines can induce objective responses in patients with metastatic malignant melanoma. We focus on the foundations of these approaches in new experimental animal models designed to test novel vaccines and report on what these new models predict for the future development of therapeutic vaccines for cancer.