Glutathione (GSH) is a crucial antioxidant involved in various cellular processes, including cell differentiation, proliferation, and apoptosis. Disruptions in GSH homeostasis are linked to cancer progression. While low GSH levels increase susceptibility to oxidative stress, high levels enhance antioxidant capacity and resistance to oxidative stress in cancer cells. This review highlights GSH's role in cancer susceptibility and sensitivity to chemotherapy. GSH maintains redox balance and protects cells from oxidative damage. Elevated GSH levels are associated with increased cancer cell growth and resistance to chemotherapy. GSH depletion, achieved through inhibitors like buthionine sulfoximine (BSO), can sensitize cancer cells to chemotherapy. However, BSO's non-selective effects limit its clinical use. GSH also influences drug resistance through mechanisms involving GCL activity, GSTs, and Nrf2 signaling. GSH depletion can enhance the effectiveness of chemotherapeutic agents by increasing oxidative stress. GSH-modulating agents, such as GSH analogs and inhibitors of GGT, are being explored for their potential in cancer therapy. The role of GSH in chemoresistance is complex, with both protective and sensitizing effects. Targeting GSH pathways offers promising therapeutic strategies for overcoming cancer progression and chemoresistance.Glutathione (GSH) is a crucial antioxidant involved in various cellular processes, including cell differentiation, proliferation, and apoptosis. Disruptions in GSH homeostasis are linked to cancer progression. While low GSH levels increase susceptibility to oxidative stress, high levels enhance antioxidant capacity and resistance to oxidative stress in cancer cells. This review highlights GSH's role in cancer susceptibility and sensitivity to chemotherapy. GSH maintains redox balance and protects cells from oxidative damage. Elevated GSH levels are associated with increased cancer cell growth and resistance to chemotherapy. GSH depletion, achieved through inhibitors like buthionine sulfoximine (BSO), can sensitize cancer cells to chemotherapy. However, BSO's non-selective effects limit its clinical use. GSH also influences drug resistance through mechanisms involving GCL activity, GSTs, and Nrf2 signaling. GSH depletion can enhance the effectiveness of chemotherapeutic agents by increasing oxidative stress. GSH-modulating agents, such as GSH analogs and inhibitors of GGT, are being explored for their potential in cancer therapy. The role of GSH in chemoresistance is complex, with both protective and sensitizing effects. Targeting GSH pathways offers promising therapeutic strategies for overcoming cancer progression and chemoresistance.