AbstractGlioblastoma, formerly known as glioblastoma multiforme (GBM), is the most frequent and most aggressive brain tumour in adults. The brain is an immunopriviledged organ, and the blood‐brain barrier shields the brain from immune surveillance. In this review, we discuss the composition of the immunosuppressive tumour micromilieu and potential immune escape mechanisms in GBM. In this respect, we focus on the role of the NKG2D receptor/ligand system. NKG2D ligands are frequently expressed on GBM tumour cells and can activate NKG2D‐expressing killer cells including NK cells and γδ T cells. Soluble NKG2D ligands, however, contribute to tumour escape from immunological attack. We also discuss the current immunotherapeutic strategies to improve the survival of GBM patients. Such approaches include the modulation of the NKG2D receptor/ligand system, the application of checkpoint inhibitors, the adoptive transfer of ex vivo expanded and/or modified immune cells or the application of antibodies and antibody constructs to target cytotoxic effector cells in vivo. In view of the multitude of pursued strategies, there is hope for improved overall survival of GBM patients in the future.