The endoplasmic reticulum stress response (ESR) is essential for maintaining cellular homeostasis in response to noxious internal and external stimuli. In malignant gliomas, ESR is induced by a low nutrient, hypoxic microenvironment, compounded by external chemotherapy and radiation therapy. Powerful protective mechanisms, including induction of the ER chaperone glucose-regulated protein 78 (GRP78), protect the glioma cells from undergoing apoptosis. This chapter reviews the ESR and how it may be modulated to induce apoptosis in malignant gliomas. Downregulation of protective mechanisms such as GRP78 may be obtained with drugs such as the green tea extract epigallocatechin gallate (EGCG), leading to increased apoptosis when glioma cells are treated with the chemotherapeutic agent temozolomide (TMZ). Conversely, glioma apoptosis may also be induced by increasing ER stress to overwhelming levels with inhibitors of sarcoplasmic/ER calcium ATPase (SERCA) such as celecoxib and dimethyl-celecoxib. Protease inhibitors such as nelfinavir also inhibit proteasome activity, leading to accumulation of misfolded proteins, triggering ER stress. These modulations of the ESR may thus lead to chemotherapy or radiation sensitization of malignant gliomas. Further understanding of the ESR in glioma cells may lead to new treatments for this currently incurable cancer.