Cancer is the second leading cause of death globally. Neoantigens are optimal targets for immunotherapy against cancers which are created by abnormal DNA sequences of tumor cells due to genome mutation, gene fusion, codon insertion/deletion, or viral infections. Identifying cancer-specific molecular antibodies is a significant challenge in developing targeted cancer therapies. Therapeutic cancer vaccines are being developed to target neoantigens in solid tumors through different delivery methods. Neoantigens are crucial in individualized adoptive T-cell therapies. Equipping T cells to recognize neoantigens unique to malignant cells can mitigate severe side effects in ACT. Neoantigen vaccines have been shown to be safe with minimal adverse events in clinical trials. However, the subsequent survival rate is still suboptimal, possibly because most trials involve patients with advanced-stage cancer. Clinical trials have suggested combination therapy to enhance the potency of neoantigen vaccines. Neoantigens exhibit high immunogenicity and do not induce toxicity in normal tissues; however, their use is limited to certain types of cancer, including anal, nasopharyngeal, cervical, and head and neck cancer. This chapter investigates the potential of neoantigen-targeted immunotherapies in rare cancers.