Abstract Restoring T cell–mediated antitumor immunity by targeting immune checkpoint inhibitors in head and neck squamous cell carcinoma (HNSCC) results in immunomodulation and durable remissions. However, the overall response rate to these immunotherapies in HNSCC is only approximately 20%. This raises the possibility that immunologic intervention earlier in the HNSCC continuum, such as in oral premalignant lesions (OPL) could elicit an increased therapeutic response. New experimental studies suggest that immune therapies can be used for HNSCC prevention rather than therapy. Given the current excitement for precision medicine, these findings support the future development of multimodality approaches for preventive immune oncology. Cancer Prev Res; 10(12); 681–3. ©2017 AACR. See related article by Jin Wang, et al., p. 684