Glutathione (GSH) is a crucial antioxidant in living organisms, maintaining cellular redox homeostasis and detoxifying xenobiotics. However, GSH plays both beneficial and detrimental roles in cancer progression and treatment resistance. Excess GSH promotes tumor progression and metastasis, while it also confers therapeutic resistance to cancer cells. This review discusses recent studies on the role of GSH in tumor initiation, progression, and treatment resistance. Targeting GSH synthesis or utilization represents a potential strategy to enhance the sensitivity of tumor cells to chemotherapy and radiotherapy. The regulation of GSH levels through various pathways, including the γ-glutamyl cycle, amino acid availability, and the NRF2-KEAP1 pathway, is also discussed. Understanding these mechanisms can inform the development of targeted therapies to improve treatment outcomes in cancer patients.Glutathione (GSH) is a crucial antioxidant in living organisms, maintaining cellular redox homeostasis and detoxifying xenobiotics. However, GSH plays both beneficial and detrimental roles in cancer progression and treatment resistance. Excess GSH promotes tumor progression and metastasis, while it also confers therapeutic resistance to cancer cells. This review discusses recent studies on the role of GSH in tumor initiation, progression, and treatment resistance. Targeting GSH synthesis or utilization represents a potential strategy to enhance the sensitivity of tumor cells to chemotherapy and radiotherapy. The regulation of GSH levels through various pathways, including the γ-glutamyl cycle, amino acid availability, and the NRF2-KEAP1 pathway, is also discussed. Understanding these mechanisms can inform the development of targeted therapies to improve treatment outcomes in cancer patients.