Glutathione-S-Transferases (GSTs) have primarily been thought to be xenobiotic metabolizing enzymes that protect cells from toxic drugs and environmental electrophiles. However, in last three decades, these enzymes have emerged as the regulators of oxidative stress–induced signaling and toxicity. 4-Hydroxy-trans 2-nonenal (HNE) an end-product of lipid peroxidation, has been shown to be a major determinant of oxidative stress–induced signaling and toxicity. HNE is involved in signaling pathways, including apoptosis, proliferation, modulation of gene expression, activation of transcription factors/repressors, cell cycle arrest, and differentiation. In this article, available evidence for a major role of GSTs in the regulation of HNE-mediated cell signaling processes through modulation of the intracellular levels of HNE is discussed.