Abstract: Glutathione (GSH) is the most important small- molecule, active oligopeptide in the maintenance of redox balance. GSH contributes to antioxidant and thiol equilibrium, as well as modulates the activities of many signaling molecules and redox-sensi-tive transcription factors by S-glutathionylation. Several studies have shown that the GSH level increased in various tumors. Additional -ly, increased GSH significantly contributes to drug resistance by eliminating ROS, detoxifying drugs, or participating in DNA repair. GSH-related metabolic enzymes are overexpressed in resistant cells, thereby regulating cellular response to chemotherapy drugs. Deple-tion of GSH or downregulation of GSH-related metabolic enzymes may effectively reverse drug resistance and promote resistant cells to restore sensitivity. This potential indicates that the GSH antioxidant system plays an important role in drug resistance. The GSH anti -oxidant system, as a potential target for antitumor therapy and reversal of drug resistance, has recently become an attractive focus in cancer research. This paper presents a review of the role of the GSH antioxidant system in drug resistance and discusses the therapeutic strategies targeting the GSH antioxidant system.