Therapeutic cancer vaccines have been a long-sought approach to harness the exquisite specificity of the immune system to treat cancer, but until recently have not had much success as single agents in clinical trials. However, new understanding of the immunoregulatory mechanisms exploited by cancers has allowed the development of approaches to potentiate the effect of vaccines by removing the brakes while the vaccines step on the accelerator. Thus, vaccines that had induced a strong T cell response but no clinical therapeutic effect may now reach their full potential. Here, we review a number of promising approaches to cancer vaccines developed initially in mouse models and their translation into clinical trials, along with combinations of vaccines with other therapies that might allow cancer vaccines to finally achieve clinical efficacy against many types of cancer.