Immunotherapy represents an exciting approach for the treatment of glioblastoma multiforme. The success of this approach depends on the identification of tumor-specific antigens that can then be exploited to target the tumor. One such antigen, the epidermal growth factor receptor variant III (EGFRvIII) is found in up to 50% of malignant gliomas. This molecule is an interesting vaccine candidate since its expression is tumor specific. Recent preclinical, as well as clinical, studies of EGFRvIII-based vaccines suggest a promising role for immunotherapy of malignant gliomas. This review focuses on vaccines that target EGFRvIII. We review preclinical and clinical data and emphasize the immunological mechanisms involved in its therapeutic effect.