The relative decreased response of peripheral tissues to insulin (insulin resistance) is a key metabolic disturbance that predisposes a large percentage of individuals to the development of type 2 diabetes and to cardiovascular disease. As detailed in an extensive literature over the last two decades, insulin resistance co-exists in varying degrees with a variety of other key risk factors, including dyslipidemia, hypertension, and vascular inflammation, that contribute to poor cardiovascular outcomes of individuals with type 2 diabetes and metabolic syndrome. Whereas insulin resistance is generally thought of as pathology unto itself, this commentary suggests that insulin resistance is a physiological compensation to inappropriate oxidative metabolism that induces a metabolic inflammatory response. Via signaling of this inflammatory response, the protective compensation to excessive oxidative metabolism dampens metabolism by reducing insulin action, fatty acid oxidation, and eventually mitochondrial function and numbers. Such a scenario could explain the coexistence of these phenomena with obesity and reduced mitochondrial function. Recent evidence suggests that thiazolidinediones exert pharmacology through modifications of mitochondrial metabolism, preventing the metabolic inflammation and allowing the up regulation of mitochondrial biogenesis. A further understanding of these mechanisms, which are likely to involve key redox signaling events emanating from mitochondrial biochemistry, is needed to fuel new therapeutic advances for the treatment of metabolic syndrome.