Insulin resistant individuals manifest multiple disturbances in free fatty acids metabolism and have excessive lipid accumulation in insulin-target tissues. A wide range of evidence suggests that defective muscle mitochondrial metabolism, and subsequent impaired ability to oxidize fatty acids, may be a causative factor in the accumulation of intramuscular lipid and the development of insulin resistance. Such mitochondrial dysfunction includes loss of mitochondria, defects in the mitochondrial OXPHOS system and decreased rate of ATP synthesis. Stimulation of mitochondrial biogenesis appears as a strategy for the clinical management of the metabolic syndrome, by enhancing mitochondrial activity and protecting the cell against the increased flux of reduced substrates to the electron transport chain and thus reducing metabolic inflammation.