High grade malignant gliomas are genetically unstable, heterogeneous and highly infiltrative; all characteristics that lend glioma cells superior advantages in resisting conventional therapies. Unfortunately, the median survival time for patients with glioblastoma multiforme remains discouraging at 12-15 months from diagnosis. Neuroimmunologists/oncologists have focused their research efforts to harness the power of the immune system to improve brain tumor patient survival. In the past 30 years, small numbers of patients have been enrolled in a plethora of experimental immunotherapy Phase I and II trials. Some remarkable anecdotal responses to immune therapy are evident. Yet, the reasons for the mixed responses remain an enigma. The inability of the devised immunotherapies to consistently increase survival may be due, in part, to intrinsically-resistant glioma cells. It is also probable that the tumor compartment of the tumor-bearing host has mechanisms or produces factors that promote tumor tolerance and immune suppression. Finally, with adoptive immunotherapy of ex vivo activated effector cell preparations, the existence of suppressor T cells within them theoretically may contribute to immunotherapeutic failure. In this review, we will summarize our own studies with immunotherapy resistant glioma cell models, as well as cover other examined immunosuppressive factors in the tumor microenvironment and immune effector cell suppressor populations that may contribute to the overall immune suppression. An in-depth understanding of the obstacles will be necessary to appropriately develop strategies to overcome the resistance and improve survival in this select population of cancer patients.