This review introduces a special issue on glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. It is involved in the reduction of peroxides and many xenobiotic compounds, as well as the conjugation of electrophiles. Methods for assessing GSH status in cells are described, along with its synthesis and regulation. Therapeutic approaches for manipulating GSH content are also discussed. The review provides an overview of important aspects of glutathione metabolism. GSH is a major antioxidant in cells, with concentrations ranging from 1–10 mM. It is involved in the reduction of reactive oxygen species (ROS) and the conjugation of xenobiotics. GSH is also involved in the regulation of the cell cycle. The sources of oxidants include quinones, which can generate ROS through redox cycling. Phagocytes produce ROS to kill microorganisms, and GSH helps neutralize these ROS. GSH also protects against oxidative damage by reducing peroxides and other reactive species. GSH plays a key role in the reduction of hydrogen peroxide (H₂O₂) and the conjugation of electrophiles such as 4-hydroxy-2-nonenal (HNE). It also interacts with other non-enzymatic antioxidants such as vitamins E and C. The measurement of GSH and its oxidized forms (GSSG) is important for understanding oxidative stress and redox signaling. Various methods, including the use of dithionitrobenzoic acid (DTNB) and high-performance liquid chromatography (HPLC), are used to measure GSH levels. GSH synthesis involves the combination of cysteine with glutamate to produce γ-glutamylcysteine, followed by the addition of glycine to form GSH. The enzyme glutamate cysteine ligase (GCL) is responsible for the first step, and its activity is regulated by feedback inhibition by GSH. The expression of GCL is also regulated by oxidants and electrophiles, which can increase the transcription of both the modulatory and catalytic subunits. The regulation of GCL is complex and involves multiple signaling pathways, including the activation of the Jun N-terminal kinase (JNK) pathway. GSH therapeutics involve increasing GSH levels through the delivery of permeable esters or the use of non-toxic precursors such as N-acetylcysteine. Natural compounds such as curcumin and sulforaphane have also been proposed for their potential to increase GSH levels. However, none of these compounds have become major therapeutic agents. In contrast, compounds that decrease GSH and increase the susceptibility of tumors to chemotherapy or radiation have been used. GCL can be inhibited by butThis review introduces a special issue on glutathione (GSH), the most abundant low molecular weight thiol compound synthesized in cells. GSH plays critical roles in protecting cells from oxidative damage and the toxicity of xenobiotic electrophiles, and maintaining redox homeostasis. It is involved in the reduction of peroxides and many xenobiotic compounds, as well as the conjugation of electrophiles. Methods for assessing GSH status in cells are described, along with its synthesis and regulation. Therapeutic approaches for manipulating GSH content are also discussed. The review provides an overview of important aspects of glutathione metabolism. GSH is a major antioxidant in cells, with concentrations ranging from 1–10 mM. It is involved in the reduction of reactive oxygen species (ROS) and the conjugation of xenobiotics. GSH is also involved in the regulation of the cell cycle. The sources of oxidants include quinones, which can generate ROS through redox cycling. Phagocytes produce ROS to kill microorganisms, and GSH helps neutralize these ROS. GSH also protects against oxidative damage by reducing peroxides and other reactive species. GSH plays a key role in the reduction of hydrogen peroxide (H₂O₂) and the conjugation of electrophiles such as 4-hydroxy-2-nonenal (HNE). It also interacts with other non-enzymatic antioxidants such as vitamins E and C. The measurement of GSH and its oxidized forms (GSSG) is important for understanding oxidative stress and redox signaling. Various methods, including the use of dithionitrobenzoic acid (DTNB) and high-performance liquid chromatography (HPLC), are used to measure GSH levels. GSH synthesis involves the combination of cysteine with glutamate to produce γ-glutamylcysteine, followed by the addition of glycine to form GSH. The enzyme glutamate cysteine ligase (GCL) is responsible for the first step, and its activity is regulated by feedback inhibition by GSH. The expression of GCL is also regulated by oxidants and electrophiles, which can increase the transcription of both the modulatory and catalytic subunits. The regulation of GCL is complex and involves multiple signaling pathways, including the activation of the Jun N-terminal kinase (JNK) pathway. GSH therapeutics involve increasing GSH levels through the delivery of permeable esters or the use of non-toxic precursors such as N-acetylcysteine. Natural compounds such as curcumin and sulforaphane have also been proposed for their potential to increase GSH levels. However, none of these compounds have become major therapeutic agents. In contrast, compounds that decrease GSH and increase the susceptibility of tumors to chemotherapy or radiation have been used. GCL can be inhibited by but