The recognition that insulin resistance is an accompaniment to advanced dilated cardiomyopathy is a relatively recent revelation, but the consequences may be considerable for the failing heart. The failing heart develops a dependence on glucose as its preferred metabolic substrate, given the efficiency of glucose oxidation in the generation of highenergy phosphates. The increased preference for glucose oxidation requires that glucose transport and oxidation be highly regulated. Myocardial insulin resistance in advanced dilated cardiomyopathy limits both glucose uptake and oxidation and impairs the heart's ability to generate much needed adenosine triphosphate. We provide evidence of insulin resistance in dilated cardiomyopathy and explore the relationship to increased sympathetic nervous system activation, lipolysis, and the subsequent alteration in the insulin signaling cascade. Together, these data provide a growing rationale for the development of clinical strategies to overcome insulin resistance in dilated cardiomyopathy.