All tumors harbor unique mutant peptides, some of which are able to elicit T-cell–mediated immune responses. These are known as neoantigens. Lung cancers bear a heavy mutational burden and hence many potential neoantigens. Neoantigens are increasingly recognized as key mediators of tumor-specific immune activation and have been identified as potential targets for personalized cancer therapies. In this review, we discuss the current data on neoantigens in lung cancer and provide an overview of the recent advances in neoantigen-based immunotherapy. Furthermore, we look ahead to highlight the major opportunities and challenges for the clinical application of neoantigen-based treatment strategies for thoracic and other malignancies.