The treatment landscape of cancer is being quickly transformed by harnessing the power of the immune system. Its utilization has yielded remarkable responses in a wide range of malignancies and is being explored in a variety of carefully designed clinical trials, assessing both the clinical benefit and molecular biomarkers of response. Given these recent advances in systemic cancer management, focus has shifted to utilizing immunotherapy to hone in on malignant gliomas. A plethora of trials have already been devised and are currently in various stages of development and implementation. These trials investigate immunomodulatory techniques to prime, stimulate, and sustain a potent response against tumor-specific antigens. This chapter will examine these varied modalities of treatment and highlight the available data, both by appraising seminal immunotherapy clinical trials in systemic oncology, and moving into trials specifically focusing on malignant glioma. Furthermore, we will discuss criteria guiding clinical, radiographic, and immunologic parameters with respect to clinical trial development in neuro-oncology.