Primary CNS tumors, despite many advancements in the field of neurosurgery and radio-oncology, have remained universally lethal. Although, until a few years ago, immunotherapy was not considered one of the treatment options in case of these cancers, recent findings have unraveled the complex genetics, anatomy, and function of the immune compartment residing within the central nervous system (CNS), reshaping the immunotherapy paradigm. Understanding the unique aspects of immune activation and regulation within the CNS will be critical in the development of any immune-based brain tumor treatment. This new insight has ramifications for a broad spectrum of tumors that arise in the central nervous system. In this chapter, we review the features of the immune system in the context of CNS, its association with tumor development, and the current standing in immunotherapy of primary CNS cancer.