This article emphasizes intrahepatocellular and intramyocellular lipid accumulation as components of the insulin resistance syndrome. It examines the mechanisms responsible for the interrelationships among ectopic fat deposition, insulin resistance, and associated metabolic traits. These relationships are complex and vary according to diet, exercise, weight loss, and racial identity. Overall, there is a high degree of association of both intrahepatocellular and intramyocellular lipids with insulin resistance and associated cardiometabolic risk factors. It concludes that further research is necessary to determine the orchestrated roles of adipose and nonadipose tissue compartments in the regulation of insulin sensitivity, and mechanisms explaining racial differences in the insulin resistance syndrome-trait cluster.