Cancer immunotherapy includes cancer vaccination, adoptive T cell transfer (ACT) with chimeric antigen receptor (CAR) T cells, and administration of tumor-infiltrating lymphocytes and immune-checkpoint blockade such as anti-CTLA4/anti-PD1 inhibitors that can directly or indirectly target tumor neoantigens and elicit a T cell response. Accurate, rapid, and cost-effective identification of ... [Show full abstract] neoantigens, however, is critical for successful immunotherapy. Here, we review computational issues for neoantigen identification by summarizing the various sources of neoantigens and their identification from high-throughput sequencing data. Several opinions are presented to inspire further discussions toward improving neoantigen identification. Continuing efforts are required to improve the sensitivity and specificity of bona fide neoantigens, taking advantage of the development of high-throughput sequencing techniques for effective and personalized cancer immunotherapy.