Glioblastoma is the most common malignant primary brain tumor. Despite standard-of-care treatment, consisting of maximal surgical resection followed by chemoradiation, both morbidity and mortality associated with this disease remain very poor. Therefore, there is an urgent need for more efficacious and well tolerated therapies. Advancing knowledge of the intricate interplay between malignant gliomas and the immune system, coupled with the recent launch of immunotherapy research for other cancers, has led to a veritable increase in immunotherapy investigation for glioblastoma and other malignant gliomas. This clinical review highlights the recent breakthroughs in cancer immunotherapy and the complex correlation of the immune system with primary brain tumors, with special attention to multiple immunotherapy modalities currently being investigated for malignant glioma, including peptide vaccines, dendritic cell vaccines, oncolytic viruses, chimeric T-cell receptors, and checkpoint inhibitors. Cancer 2017;123:734-50. © 2016 American Cancer Society.