Exposure to a toxic chemical or poison sets off a cascade of effects, subsequent to an initial, unique biochemical event, culminating in frank pathology and, depending on dose, even death. This initial biochemical event is referred to as the seminal or primary biochemical lesion and is usually the result of an interaction between the poison or a product of its biotransformation and an enzyme or regulatory system. Identification of the primary biochemical lesion frequently defines a poison's toxic mechanism and provides a focus for developing prophylactic, antidotal or supportive therapy. I have used the primary biochemical lesion concept as a framework to guide experimentation in the study of the vesicant action of sulfur mustard. That work has led to the discovery of sulfur mustard-related protein phosphatase inhibition, the identification of thiodiglycol as a previously unknown substrate for mammalian alcohol dehydrogenases and the identification of previously unreported sulfur mustard metabolites. However, those results seem to fall into the category of downstream effects in the cascade of toxicity rather than its cause. Building on the success in reducing mustard toxicity of Dr. Thomas Sawyer in Canada and Dr. Uri Wormser in Israel, I have recently revisited the problem with an investigation of the interaction of mustard derived sulfonium ions with purine nucleotide-driven flavoenzyme reductases. The results thus far have been exciting with broad implications for the toxicology of sulfur mustard.