Vaccine studies using whole tumor cells or heterogeneous mixtures of tumor antigens provide intriguing evidence that cancer vaccines might be effective. Now it is possible to test vaccines composed of well-characterized proteins and peptides. Testing vaccine formulations composed of known and defined antigens will allow a more precise determination as to why vaccines work when they work, and why they do not work when they fail. The demonstration that human malignancy is immunogenic and the definition of human tumor antigens has set the stage for a new generation of cancer vaccines directly targeting immunogenic cancer-related peptides and proteins. Many newly defined tumor antigens are self proteins. As an example, screening existent immunity in human melanoma has identified responses to nonmutated self proteins: MAGE, MART, gp100, and tyrosinase. Tolerance to self antigens now emerges as a possible mechanism of tumor immune escape. A new puzzle has emerged for tumor immunologists to solve; how to harness immunity to "self" tumor antigens for cancer therapeutics.