Neural oncogenesis is currently incurable and invariably lethal. The development of innovative treatments for this devastating cancer will require a deeper molecular understanding of how cancer cells survive, proliferate, and escape from current therapies. In high‐grade gliomas (HGGs), glioma stem cells (GSCs) may causally contribute to tumor initiation and propagation, therapeutic resistance, and subsequent recurrence of tumors. Within a tumor mass, GSCs are enriched in a hypoxic niche in which the oxidative stress levels are substantially elevated. Paradoxically, however, recent studies suggest that GSCs appear to generate less reactive oxygen species (ROS), a chemical component responsible for elevation of oxidative stress levels. To date, molecular mechanisms for how GSCs reduce oxidative stress to allow preferential survival in hypoxic areas in tumors remains elusive. This review article summarizes recent studies on the role of ROS‐reducing enzymes, including peroxiredoxin 4, in detoxifying oxidative stress preferentially for GSCs in HGGs. In addition, the therapeutic potential of some of the recently identified antioxidant chemotherapeutic agents and avenues for future research in this area are discussed. © 2014 Wiley Periodicals, Inc.