Skeletal muscle is the largest tissue responsible for the insulin-stimulated disposal of glucose. However, identifying the link between excess body fat and impaired insulin sensitivity in skeletal muscle has been difficult. Several adipose-derived cytokines (adipokines) have been implicated in the impairment of insulin sensitivity, while adipokines such as leptin and adiponectin exert an insulin-sensitizing effect. Leptin and adiponectin have each been shown to increase fatty acid (FA) oxidation and decrease triglyceride storage in muscle, which may explain, in part, the insulin-sensitizing effect of these cytokines. Recent evidence strongly implicates an increased localization of the FA transporters to the plasma membrane (PM) as an important factor in the accumulation of intramuscular lipids with high-fat diets and obesity. Perhaps surprisingly, relatively little attention has been paid to the ability of insulin-sensitizing compounds, such as leptin and adiponectin, to decrease the abundance of FA transporters in the PM, thereby decreasing lipid accumulation. In the case of both adipokines, there is also evidence that a resistance to their ability to stimulate FA oxidation in skeletal muscle develops during obesity. One of our recent studies indicates that this development can be very rapid (i.e., within days), and precedes the increase in lipid uptake and accumulation that leads to insulin resistance. It is noteworthy that leptin resistance can be modulated by both diet and training in rodents. Further studies examining the underlying mechanisms of the development of leptin and adiponectin resistance are warranted.