Glioblastoma multiforme (GBM) is a malignant, relentless brain cancer with no known cure, and standard therapies leave significant room for the development of better, more effective treatments. Immunotherapy is a promising approach to the treatment of solid tumors that directs the patient’s own immune system to destroy tumor cells. The most widespread and successful immunologically-based cancer therapy to date involves the passive administration of monoclonal antibodies, but significant antitumor responses have also been generated with active vaccination strategies and cell-transfer therapies as well. This article summarizes the important components of the immune system, discusses the specific difficulty of immunologic privilege in the central nervous system (CNS), and reviews the variety of treatment approaches that are being attempted, with an emphasis on active immunotherapy using peptide vaccines in the treatment of GBM.