It has long been known that acute exercise can dramatically improve insulin sensitivity in previously insulin resistant muscle; however, the precise mechanisms underlying this clinically significant interaction remain unknown. Using hindlimb perfusions in obese Zucker rats, our group found that acute muscle contraction synergistically improved insulin stimulated glucose transport in skeletal muscle, but contrary to our hypothesis, these findings were not associated with either improved insulin signaling or decreased intramuscular lipid metabolites. A further analysis revealed that the improved insulin sensitivity was associated with a robust increase in mitochondrial energy flux. These findings and reports from other labs suggest that mitochondrial energy flux and mitochondrial oxidative capacity may govern insulin sensitivity and override insulin signaling defects associated with obesity. This review will discuss the effects of acute exercise to enhance insulin sensitivity in previously insulin resistant muscle and present possible novel mechanisms by which alterations in mitochondrial energy metabolism may play a regulatory role.