Glutathione (GSH) plays a crucial role in cellular processes such as cell differentiation, proliferation, and apoptosis. Disturbances in GSH homeostasis are implicated in the etiology and progression of many human diseases, including cancer. GSH deficiency increases susceptibility to oxidative stress, while elevated GSH levels enhance antioxidant capacity and resistance to oxidative stress, observed in many cancer cells. This review highlights the role of GSH and its cytoprotective effects in carcinogenesis and the sensitivity of tumors to anticancer agents. GSH is a tripeptide composed of glutamic acid, cysteine, and glycine. It is essential for maintaining intracellular redox balance and detoxifying xenobiotics and endogenous compounds. GSH levels are associated with cell proliferation and metastatic activity in various cancers. High GSH levels can protect cancer cells from oxidative stress and chemotherapy, leading to chemoresistance. Depleting GSH through agents like buthionine sulfoximine (BSO) has been explored as a strategy to sensitize tumor cells to chemotherapy. However, the nonselective effects of BSO have limited its clinical use. New approaches, such as targeting GSH-utilizing enzymes and modulating the Nrf2-ARE pathway, are being investigated to overcome chemoresistance. The modulation of GSH-based antioxidant redox systems represents a promising therapeutic strategy. GSH analogues, GGT inhibitors, and drugs targeting S-glutathionylation have shown potential in clinical trials. Further research is needed to understand the molecular pathways driven by GSH and to develop more effective therapeutic strategies against cancer progression and chemoresistance.Glutathione (GSH) plays a crucial role in cellular processes such as cell differentiation, proliferation, and apoptosis. Disturbances in GSH homeostasis are implicated in the etiology and progression of many human diseases, including cancer. GSH deficiency increases susceptibility to oxidative stress, while elevated GSH levels enhance antioxidant capacity and resistance to oxidative stress, observed in many cancer cells. This review highlights the role of GSH and its cytoprotective effects in carcinogenesis and the sensitivity of tumors to anticancer agents. GSH is a tripeptide composed of glutamic acid, cysteine, and glycine. It is essential for maintaining intracellular redox balance and detoxifying xenobiotics and endogenous compounds. GSH levels are associated with cell proliferation and metastatic activity in various cancers. High GSH levels can protect cancer cells from oxidative stress and chemotherapy, leading to chemoresistance. Depleting GSH through agents like buthionine sulfoximine (BSO) has been explored as a strategy to sensitize tumor cells to chemotherapy. However, the nonselective effects of BSO have limited its clinical use. New approaches, such as targeting GSH-utilizing enzymes and modulating the Nrf2-ARE pathway, are being investigated to overcome chemoresistance. The modulation of GSH-based antioxidant redox systems represents a promising therapeutic strategy. GSH analogues, GGT inhibitors, and drugs targeting S-glutathionylation have shown potential in clinical trials. Further research is needed to understand the molecular pathways driven by GSH and to develop more effective therapeutic strategies against cancer progression and chemoresistance.