Surgical resection continues to predominate as the primary treatment modality in glioblastoma (GBM). Effective chemotherapeutic/biologic agents capable of targeting GBM have yet to be developed in part because of the exceptionally heterogeneous nature and unique microenvironmental conditions associated with this malignant neoplasm. Temozolomide and bevacizumab represent the only U.S. Food and Drug Administration–approved agents for primary and recurrent GBM, respectively. Given the high therapeutic resistance of GBM to current therapies, as well as the failure of bevacizumab to prolong overall survival, new therapeutic agents are urgently warranted and are now in the preclinical and clinical phases of development. Accordingly, clinical trials evaluating the efficacy of immune checkpoint inhibition, chimeric antigen receptor T cell therapy, virotherapies, and tumor vaccination therapy are all under way in GBM. Herein, we review the application of current/novel therapeutics in GBM and in so doing attempt to highlight the most promising solutions to overcome current failures.