We hypothesize that nutrition can modulate the toxicity of environmental pollutants and thus modulate health and disease outcome associated with chemical insult. There is now increasing evidence that exposure to persistent organic pollutants, such as PCBs, can contribute to the development of inflammatory diseases such as atherosclerosis. Activation, chronic inflammation, and dysfunction of the vascular endothelium are critical events in the initiation and acceleration of atherosclerotic lesion formation. Our studies indicate that an increase in cellular oxidative stress and an imbalance in antioxidant status are critical events in PCB-mediated induction of inflammatory genes and endothelial cell dysfunction. Furthermore, we have found that specific dietary fats can further compromise endothelial dysfunction induced by selected PCBs and that antioxidant nutrients (such as vitamin E and dietary flavonoids) can protect against endothelial cell damage mediated by these persistent organic pollutants. Our recent data suggest that membrane lipid rafts such as caveolae may play a major role in the regulation of PCB-induced inflammatory signaling in endothelial cells. In addition, PCB- and lipid-induced inflammation can be down-regulated by ligands of anti-atherogenic peroxisome proliferator-activated receptors (PPARs). We hypothesize that PCBs contribute to an endothelial inflammatory response in part by down-regulating PPAR signaling. Our data so far support our hypothesis that antioxidant nutrients and related bioactive compounds common in fruits and vegetables protect against environmental toxic insult to the vascular endothelium by down-regulation of signaling pathways involved in inflammatory responses and atherosclerosis. Even though the concept that nutrition may modify or ameliorate the toxicity of environmental chemicals is provocative and warrants further study, the implications for human health could be significant. More research is needed to understand observed interactions of PCB toxicity with nutritional interventions.