Abnormalities in muscle fatty acid (FA) metabolism, particularly the accumulation of intramuscular lipids and a decreased capacity to oxidize FA, are strongly linked to the development of insulin resistance. There are numerous hormones that have been demonstrated to regulate skeletal muscle FA metabolism. Currently, there is much interest in the role of cytokines derived from adipose tissue (adipokines) as a potential link between the accumulation of total body fat mass and the development of insulin resistance. Leptin, the product of the ob gene, is a peptide hormone that is produced primarily by adipose tissue and been shown to regulate food intake and energy expenditure in rodents. In ob/ob mice, the absence of leptin results in a phenotype that is characterized by obesity and insulin resistance, which can be normalized with daily injection of recombinant leptin. However, in most cases of human obesity, there is an elevation in the concentration of circulating leptin; reports of very low plasma leptin are relatively rare. This has been interpreted as an indication of the development of leptin resistance. However, very few studies have examined the development of leptin resistance in skeletal muscle, which, by mass, is the most important tissue involved in whole-body insulin-stimulated glucose clearance. Leptin has been demonstrated to have profound effects on skeletal muscle FA metabolism, resulting in an increase in the capacity to oxidize FA and a lowering of triacylglycerol (IMTAG) stores (Fig. 1). Thus, the development of leptin resistance in skeletal muscle may lead to insulin resistance in this tissue by allowing the accumulation of intramuscular lipids and disruption of the insulin signaling pathway (Fig. 2). It is further hypothesized that various lifestyle factors known to alter insulin sensitivity may elicit their effect at least in part by altering leptin sensitivity in skeletal muscle. Thus, high-fat diets, which are known to lead to obesity and insulin resistance, should impair leptin sensitivity in skeletal muscle, whereas aerobic training, which improves insulin sensitivity, would be expected to improve leptin sensitivity. Initial results from our laboratory have supported these hypotheses.