Antidiabetic effects associated with salicylates have been known for years, although the underlying mechanisms were not understood. We have been reinvestigating these effects in the light of recent discoveries in the areas of signal transduction and insulin resistance. Our findings showed that signaling pathways leading to I kappa B kinase beta (IKK beta) and NF-kappa B are activated in insulin-responsive tissues of obese and high-fat-fed animals. Since activation correlates with the development of insulin resistance, we asked whether signaling through this might be involved in the pathogenesis of insulin resistance. Heterozygous gene deletion (Ikk beta+/-) or salicylates, working as IKK beta inhibitors, improved insulin sensitivity in insulin-resistant rodent models. Furthermore, high doses of salicylates (aspirin or salicylate) improved insulin sensitivity in patients with type II diabetes. Our studies implicate an inflammatory process in the pathogenesis of insulin resistance in obesity and type II diabetes mellitus and identify the IKK beta/NF-kappa B pathway as a molecular mediator of insulin resistance and pharmacological target for insulin sensitization.