evidence: In terms of lives saved, vaccines have been the greatest triumphs of medicine. Since their first use by Edward Jenner and his contemporaries, vaccines have been developed to prevent numerous infectious diseases by training the immune system to rapidly and specifically destroy the offending pathogen thus preventing disease. The application of vaccines to cancer is an obvious extension of their utility, but attempts to achieve this have been a frustrating journey. An exception is the generation of prophylactic vaccines against hepatitis B virus (HBV) and human papillomavirus (HPV), which are causes of liver and cervical cancer, respectively.1,2 These prophylactic vaccines have been successful because they circumvent three major challenges facing the development of therapeutic cancer vaccines: (1) low immunogenicity; (2) established disease burden; and (3) the immunosuppressive tumor microenvironment. Much of the work on therapeutic cancer vaccines has taken aim at tumor-associated antigens (TAAs), which are aberrantly expressed self-antigens. Since high-affinity T cells recognizing self-antigens are eliminated during development by our immune system’s central and peripheral tolerance mechanisms, TAA-directed cancer vaccines face the challenge of activating any remaining, low affinity T cells. [...] Castle, J. C. et al. Exploiting the mutanome for tumor vaccination. Cancer Res.72, 1081–1091 (2012). [...] Sahin, U. et al. Personalized RNA mutanome vaccines mobilize poly-specific therapeutic immunity against cancer. Nature547, 222–226 (2017).