Synthetic xenobiotics such as herbicides elicit the generation of reactive oxygen intermediates (ROIs) in plants, which induce antioxidant defences, notably the production of glutathione (GSH) and glutathione transferases (GSTs). GSTs also play an important role in catalysing the conjugation of xenobiotics with GSH, which leads to their detoxification. We have been interested in the multiple roles of GSTs in counteracting xenobiotic-induced stress in plants and the induction of these enzymes by herbicide safeners, which act without the need for large-scale ROI accumulation. Safeners are compounds that enhance herbicide tolerance in cereals and are known to induce the expression of different classes of xenobiotic-detoxifying enzymes, which we have collectively termed the xenome. It has been proposed that safeners act by enhancing the detoxification of xenobiotics. However, we propose that safeners primarily protect plants by inducing a specific subset of antioxidant responses that relate to the endogenous functions of the xenome. Using GSTs as an example of multifunctional protective proteins, we examine this paradigm for safener action and what it tells us about antioxidant signalling pathways in plants.