The dismal prognoses suffered by malignant primary brain tumor (glioma) patients remain unchanged over the past two decades despite significant improvements in the treatment of distinct tumors. Immunotherapy, and vaccine therapy in particular, represents a promising experimental approach to treat malignant gliomas, but major challenges still remain to render vaccination clinically effective. These challenges include diminishing the risk of pathologic autoimmunity, and identifying the cellular basis of clinical vaccine benefits. Addressing such challenges should eventually help increase the proportion of patients experiencing clinical vaccine benefits. Recent studies in glioma patients have characterized tumor antigens on human gliomas, identified some of the immune cells involved in beneficial anti-glioma immunity, and examined how gliomas may be altered by sub-lethal immune influences. This has provided a glimpse of the strength to which immunity influences glioma clinical outcome, and resurrects hope that clinically effective vaccines to treat these tumors is within reach. Insight into the complex dynamics of immune-tumor interactions promises to extend this reach by delineating mechanisms of immune synergy with other forms of treatment.