Tumor cells frequently express antigens that allow them to be specifically targeted and destroyed by the immune system. Many tumor immunotherapy clinical trials have been conducted, directed at several types of cancer using myriad antigens and multiple immunization strategies. Despite this, only one therapeutic cancer vaccine, sipuleucel-T, has been approved. A groundbreaking study by Jaini et al. recently demonstrated that prophylactic immunization against a breast cancer associated antigen can prevent tumor development, and is far more effective than therapeutic vaccination. This study highlights the urgent need to rethink the clinical testing of tumor immunotherapies; it is time to consider clinical trials of cancer vaccines in the prophylactic setting. See article at Mol. Interv. 2010, 10:197-203.