Neoantigens are tumor-specific proteins and peptides that can be highly immunogenic. Immune-mediated tumor rejection is strongly associated with cytotoxic responses to neoantigen-derived peptides in noncovalent association with self-HLA molecules. Neoantigen-based therapies, such as adoptive T cell transfer, have shown the potential to induce remission of treatment-resistant metastatic disease in select patients. Cancer vaccines are similarly designed to elicit or amplify antigen-specific T cell populations and stimulate directed antitumor immunity, but the selection and prioritization of the neoantigens remains a challenge. Bioinformatic algorithms can predict tumor neoantigens from somatic mutations, insertion-deletions, and other aberrant peptide products, but this often leads to hundreds of potential neoepitopes, all unique for that tumor. Selecting neoantigens for cancer vaccines is complicated by the technical challenges of neoepitope discovery, the diversity of HLA molecules, and intratumoral heterogeneity of passenger mutations leading to immune escape. Despite strong preclinical evidence, few neoantigen cancer vaccines tested in vivo have generated epitope-specific T cell populations, suggesting suboptimal immune system activation. In this chapter, we review factors affecting the prioritization and delivery of candidate neoantigens in the design of therapeutic and preventive cancer vaccines and consider synergism with standard chemotherapies.