Increased release and action of proinflammatory cytokines are thought to be responsible for the occurrence of insulin resistance in inflammatory and metabolic diseases including obesity-linked diabetes. Recent work has identified several signal transduction pathways activated by cytokines which can impede on insulin receptor signaling in skeletal muscle, liver, and adipose cells. A majority of these complex and interrelated pathways appear to converge at the level of insulin receptor substrate-1 by promoting its serine phosphorylation in order to mediate heterologous inhibition of insulin receptor substrate-1 signaling which, in turn, counterregulates the insulin response. Other possible mechanisms of insulin resistance in cytokine-treated cells include nitration of insulin receptor substrate-1 tyrosine residues by nitric oxide-derived reactive nitrogen species as well as direct interference with insulin signaling molecules further downstream such as protein kinase B/Akt. A detailed knowledge of the complex network of intracellular signaling pathways triggered by cytokines may be instrumental in the development of new approaches to prevent insulin resistance in acute and chronic inflammatory settings.