The current epidemic of the metabolic syndrome in the developed world is largely due to overnutrition and lack of physical activity. However, the underlying causes by which chronic overnutrition interacts with genotype and physical inactivity to generate the metabolic syndrome phenotype are complex, and include multiple metabolic and physiological alterations. Mitochondrial oxidative stress has been suggested to contribute to the metabolic syndrome, but the mechanisms and significance are unclear. Here we review how disruption of mitochondrial metabolism and increased oxidative stress may occur during overnutrition coupled with limited physical activity. From this we suggest a unifying hypothesis to integrate what is known about mitochondrial involvement in the metabolic syndrome that points to testable hypotheses and novel therapeutic approaches.