Concerted efforts of tumor immunologists over more than two decades contributed numerous well-defined tumor antigens, many of which were promptly developed into cancer vaccines and tested in animal models and in clinical trials. Encouraging results from animal models were seldom recapitulated in clinical trials. The impediment to greater success of these vaccines has been their exclusive use for cancer therapy. What clinical trials primarily revealed were the numerous ways in which cancer and/or standard treatments for cancer could suppress the patient's immune system, making it very difficult to elicit effective immunity with therapeutic vaccines. In contrast, there is an extensive database of information from experiments in appropriate animal models showing that prophylactic vaccination is highly effective and safe. There are also studies that show that healthy people have immune responses against antigens expressed on tumors, some generated in response to viral infections and others in response to various nonmalignant acute inflammatory events. These immune responses do not appear to be dangerous and do not cause autoimmunity. Epidemiology studies have shown that these immune responses may reduce cancer risk significantly. Vaccines based on tumor antigens that are expressed differentially between tumors and normal cells and can stimulate immunity, and for which safety and efficacy have been proved in animal models and to the extent possible in therapeutic clinical trials, should be considered prime candidates for prophylactic cancer vaccines.