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Also owing to the limited efficacy of targeted therapies, there has been a renewed interest in targeting gliomas with immunotherapy. But despite considerable efforts using sophisticated approaches, proof of efficacy beyond case studies is still lacking. The purpose of this review is to summarize and discuss current immunotherapeutic approaches and efforts to understand mechanisms of response and resistance.The recent failure of large randomized clinical trials using targeted vaccines and checkpoint inhibitors to improve clinical outcome have underlined the grand challenges in this therapeutic arena and illustrated the necessity to understand the biology of immunotherapeutic interventions before conducting large randomized studies. However, these failures should not distract us from continuing to optimize immunotherapeutic concepts. The recent developments in transgenic T cell technologies and personalized vaccines but also rational combinatorial approaches offer tremendous opportunities and should be exploited carefully in early scientifically driven clinical trials.A profound understanding of the cellular and molecular mechanisms of response and resistance to immunotherapy to be gained from these thoroughly designed clinical trials will be essential to carve out successful strategies in selected patient populations.