Glutathione-S-transferases (GSTs) are Phase II detoxification enzymes that catalyze the conjugation of glutathione (GSH) to various electrophilic compounds. They are divided into two families: microsomal and cytosolic. Cytosolic GSTs are highly polymorphic and play a regulatory role in the mitogen-activated protein (MAP) kinase pathway, which is involved in cellular survival and death signals. GSTs have been implicated in chemotherapy resistance, possibly through direct detoxification and inhibition of the MAP kinase pathway. GSTs are promising therapeutic targets because specific isozymes are overexpressed in many tumors and may contribute to other diseases. GSTs regulate the MAP kinase pathway by interacting with proteins like JNK1 and ASK1, which are activated under stress. GST overexpression can lead to drug resistance, as the selecting drugs may not be substrates for GSTs. Inhibitors like ethacrynic acid and TLK199 have been developed to modulate GST activity, enhancing drug sensitivity. GSTs also play a role in myeloproliferative diseases and parasitic infections. GST-activated prodrugs are being explored as potential cancer therapies, with TLK286 showing promise in clinical trials. GSTs are also targets for vaccine development against parasitic diseases. Overall, GSTs have dual roles in metabolism and signaling, making them important in cancer treatment and other diseases.Glutathione-S-transferases (GSTs) are Phase II detoxification enzymes that catalyze the conjugation of glutathione (GSH) to various electrophilic compounds. They are divided into two families: microsomal and cytosolic. Cytosolic GSTs are highly polymorphic and play a regulatory role in the mitogen-activated protein (MAP) kinase pathway, which is involved in cellular survival and death signals. GSTs have been implicated in chemotherapy resistance, possibly through direct detoxification and inhibition of the MAP kinase pathway. GSTs are promising therapeutic targets because specific isozymes are overexpressed in many tumors and may contribute to other diseases. GSTs regulate the MAP kinase pathway by interacting with proteins like JNK1 and ASK1, which are activated under stress. GST overexpression can lead to drug resistance, as the selecting drugs may not be substrates for GSTs. Inhibitors like ethacrynic acid and TLK199 have been developed to modulate GST activity, enhancing drug sensitivity. GSTs also play a role in myeloproliferative diseases and parasitic infections. GST-activated prodrugs are being explored as potential cancer therapies, with TLK286 showing promise in clinical trials. GSTs are also targets for vaccine development against parasitic diseases. Overall, GSTs have dual roles in metabolism and signaling, making them important in cancer treatment and other diseases.