Utilizing the host immune system to eradicate cancer cells has been the most investigated subject in the cancer research field in recent years. However, most of the studies have focused on highly variable responses from immunotherapies such as immune checkpoint inhibitors, from which the majority of patients experienced no or minimum clinical benefit. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer‐specific immune targets. Highly tumor‐specific antigens, neoantigens, are generated by somatic mutations that are not present in normal cells. It is plausible that by targeting antigens with high tumor‐specificity, such as neoantigens, the likelihood of toxic effects is very limited. However, understanding the interaction between neoantigens and the host immune system remains a significant challenge. This review focuses on the potential use of neoantigen‐targeted immunotherapies in cancer treatment and the recent progress of different strategies in predicting, identifying, and validating neoantigens. Successful identification of highly tumor‐specific antigens accelerates the development of personalized immunotherapy with no or minimum adverse effects and with a broader coverage of patients. Advances in genomic sequencing technologies have improved our understanding of immunopharmacogenomics and allowed us to identify novel cancer‐specific immune targets, including highly tumor‐specific neoantigens, which are generated by somatic mutations. However, understanding the interaction between neoantigens and the host immune system has remained to be a big challenge. This review focuses on the potential use of neoantigen‐targeted immunotherapies in cancer treatment and the recent progresses of the different strategies in predicting, identifying and validating neoantigens to develop personalized cancer immunotherapy.