Obesity and the related metabolic syndrome have become a worldwide epidemic. Inactivity appears to be a primary causative factor in the pathogenesis of this obesity and metabolic syndrome. There are two possible, perhaps not mutually exclusive, events that may lead to intramyocellular lipid accumulation and mitochondrial dysfunction in patients with obesity. First, obesity, with high intake-associated lipid accumulation in muscle may interfere with cellular mitochondrial function through generation of reactive oxygen species leading to lipid membrane peroxidative injury and disruption of mitochondrial membrane-dependent enzymes. This in turn leads to impaired oxidative metabolism. Secondly, a primary defect in mitochondrial oxidative metabolism may be responsible for a reduction in fatty acid oxidation leading to intramyocellular lipid accumulation as a secondary event. Non-invasive techniques such as proton (1H) and phosphorus (31P) magnetic resonance spectroscopy, coupled with specific magnetic resonance imaging techniques, may facilitate the investigation of the effects of various ergometric interventions on the pathophysiology of obesity and the metabolic syndrome. Exercise has positive effects on glucose metabolism, aerobic metabolism, mitochondrial density, and respiratory chain proteins in patients with metabolic syndrome, and we propose that this may be due to the exercise effects on AMP kinase, and a prospective physiological mechanism for this benefit is presented. A physiological model of the effect of intramyocellular lipid accumulation on oxidative metabolism and insulin mediated glucose uptake is proposed.