Glioblastoma remains one of the most challenging and devastating cancers, with only a very small proportion of patients achieving 5-year survival. The current standard of care consists of surgery, followed by radiation therapy with concurrent and maintenance chemotherapy with the alkylating agent temozolomide. To date, this drug is the only one that provides a significant survival benefit, albeit modest, as patients end up acquiring resistance to this drug. As a result, tumor progression and recurrence inevitably occur, leading to death. Several factors have been proposed to explain this resistance, including an upregulated antioxidant system to keep the elevated intracellular ROS levels, a hallmark of cancer cells, under control. In this review, we discuss the mechanisms of chemoresistance -including the important role of glioblastoma stem cells-with emphasis on antioxidant defenses and how agents that impair redox balance (i.e.: sulfasalazine, erastin, CB-839, withaferin, resveratrol, curcumin, chloroquine, and hydroxychloroquine) might be advantageous in combined therapies against this type of cancer.