Traditional views on the metabolic derangements underlying insulin resistance and Type 2 diabetes have been largely "glucocentric" in nature, focusing on the hyperglycemic and/or hyperinsulinemic states that result from impaired glucose tolerance. But in addition to glucose intolerance, there is a coordinated breakdown in lipid dynamics in individuals with insulin resistance, manifested by elevated levels of circulating free fatty acids, diminished rates of lipid oxidation, and excess lipid accumulation in skeletal muscle and/or liver. This review examines the premise that an oversupply and/or accumulation of lipid directly inhibits insulin action on glucose metabolism via changes at the level of substrate competition, enzyme regulation, intracellular signaling, and/or gene transcription. If a breakdown in lipid dynamics is causal in the development of insulin resistance (rather than a coincidental feature resulting from it), it should be possible to demonstrate that interventions that improve lipid homeostasis cause reciprocal changes in insulin sensitivity. Accordingly, the efficacy of aerobic endurance training in human subjects in mediating the association between deranged lipid metabolism and insulin resistance will be examined. It will be demonstrated that aerobic exercise training is a potent and effective primary intervention strategy in the prevention and treatment of individuals with insulin resistance.