Prognosis for patients with glioblastoma (GBM), the most common high-grade primary central nervous system (CNS) tumor, remains discouraging despite multiple discoveries and clinical advances. Immunotherapy has emerged as a promising approach to GBM therapy as the idea the human CNS is immunoprivileged is being challenged. Early clinical studies of vaccine-based approaches have been encouraging, but further investigation is required before these therapies become clinically meaningful. A key challenge in immunotherapy involves identification of target antigens that are specific and sensitive for GBM. Here we discuss tumor-associated antigens that have been targeted for GBM therapy, strategies for discovery of novel antigens, and the theory of epitope spreading as it applies to GBM immunotherapy.