Endoplasmic reticulum (ER) stress disrupts among others protein homeostasis in cells leading to the activation of the unfolded protein response (UPR) that is crucial for restoring this balance and cell survival. Hypoxia, reactive oxygen species and nutrient deprivation, conditions commonly present in the tumor microenvironment, are well-known triggers of the UPR. Apart from being an adaptive response, recently the UPR has been implicated in oncogenesis. Here we review the current understanding of the UPR in the most life threatening brain tumor in adults, glioblastoma multiforme (GBM). The UPR is controlled by BiP/GRP78 and three different sensors, PERK, IRE1 and ATF6. In orthotopic GBM mouse models IRE1 was reported to control angiogenesis, invasion and mesenchymal differentiation. Furthermore, PERK also was found to stimulate GBM growth. However, a direct role of the UPR in gliomagenesis remains to be demonstrated. Patient samples display chronic activation of the UPR and in vitro standard chemo- and radiotherapy partially act by aggravating ER stress leading to cell death. The UPR has been linked to enhanced sensitivity for apoptosis-inducing agents such as TRAIL and MDA-7. A number of agents such as proteasome inhibitors and several natural products were reported to exert cytotoxicity by enhancing ER stress in GBM cells, and some demonstrated activity in clinical studies. Finally, ER stress was suggested to be implicated in the maintenance of homeostasis in GBM stem cells. Taken together, the UPR appears to play an important role in GBM tumor progression and is a promising target for developing novel therapeutic interventions.