Environmental factors including diet, sedentary lifestyle and exposure to pollutants largely influence human health throughout life. Cellular and molecular events triggered by an exposure to environmental pollutants are extremely variable and depend on the age, the chronicity and the doses of exposure. Only a fraction of all relevant mechanisms involved in the onset and progression of pathologies in response to toxicants has probably been identified. Mitochondria are central hubs of metabolic and cell signaling responsible for a large variety of biochemical processes, including oxidative stress, metabolite production, energy transduction, hormone synthesis, and apoptosis. Growing evidence highlights mitochondrial dysfunction as a major hallmark of environmental insults. Here, we present mitochondria as crucial organelles for healthy metabolic homeostasis and whose dysfunction induces critical adverse effects. Then, we review the multiple mechanisms of action of pollutants causing mitochondrial toxicity in link with chronic diseases. We propose the Aryl hydrocarbon Receptor (AhR) as a model of “exposome receptor”, whose activation by environmental pollutants leads to various toxic events through mitochondrial dysfunction. Finally, we provide some remarks related to mitotoxicity and risk assessment.