Tumor vaccines have been an attractive concept in the immunotherapy of cancer based on the central role of tumor-associated antigens in allowing the immune system to recognize cancer cells and the large variety of platforms in which to present such antigens to the immune system. Early clinical studies of vaccines, however, were largely disappointing. Recent evidence that cancer-mediated T cell suppression may prevent T cell activation is leading to renewed interest in vaccine development. The use of T cell checkpoint inhibitors alone has revolutionized the contemporary treatment of human cancer, and has suggested that the emergence of neoantigens may be an important biomarker of therapeutic response. Thus, the possibility of using more personalized vaccines targeting relevant neoantigens alone and in combination with T cell checkpoint blockade is a new area of active clinical investigation. In this review we will discuss the central role of antigens in tumor immunotherapy, describe how vaccines may be developed in the context of modern genomic profiling of tumor cells and provide a forward looking perspective on how tumor vaccines may be incorporated into the current landscape of cancer therapy.