Primary brain tumors account for a minor fraction of cancer diagnoses made worldwide and remain one of the most difficult to treat. Despite ongoing efforts to improve the quality of life and overall survival of these patients, current multimodality therapy has achieved only modest gains; the median survival is approximately 14 months among patients with the deadliest form of primary brain tumor, glioblastoma multiforme. Although the brain has been long considered an immunologically privileged organ, there is increased awareness of and appreciation for the complex interplay between the nervous system and the immune system in the setting of many disease states, including neoplastic. Although the concept of harnessing the specificity, activity, and memory of the immune system toward the treatment of brain tumors has been in existence for several decades and the neuro-oncology literature holds many publications that once promised of a breakthrough, only recently has a strategy emerged that addresses many of the limitations identified through past failures. It is with cautious optimism that the authors review the past and discuss the present status of immunotherapy and its role in the management of patients with primary brain tumors.