The article reviews the historical and molecular perspectives on the link between inflammation and insulin resistance in the development of type 2 diabetes (T2D). Over a century ago, high doses of salicylates were found to lower glucose levels in diabetic patients, suggesting a connection between inflammation and T2D. Recent studies have identified tissue macrophages as key players in this process. The evolving concept of insulin resistance and T2D as having immunological components has led to new opportunities for using anti-inflammatory strategies to correct the metabolic consequences of excess adiposity. Molecular pathways linking inflammation and insulin resistance include the activation of JNK and IKKβ/NF-κB, which promote insulin resistance through various mechanisms. Proinflammatory cytokines such as TNF-α, IL-6, and resistin, produced by adipocytes and macrophages, activate these pathways. Inflammation is also closely linked to the pathogenesis of atherosclerosis, suggesting that it might be a common denominator linking obesity to its pathological sequelae. The liver and skeletal muscle are other major sites of insulin resistance in obesity and T2D. While inflammation is activated in the liver and skeletal muscle, it does not appear to be a primary site of initiation. Instead, these tissues are targets of inflammation-induced insulin resistance. Future trials to target inflammation include evaluating the efficacy of anti-inflammatory drugs such as high-dose salicylates, specific JNK or IKKβ inhibitors, and compounds that block TNF-α, IL-6, TLR, or chemokine signaling. These approaches may provide clinical benefits to a large number of persons affected by the obesity epidemic and related metabolic disorders.The article reviews the historical and molecular perspectives on the link between inflammation and insulin resistance in the development of type 2 diabetes (T2D). Over a century ago, high doses of salicylates were found to lower glucose levels in diabetic patients, suggesting a connection between inflammation and T2D. Recent studies have identified tissue macrophages as key players in this process. The evolving concept of insulin resistance and T2D as having immunological components has led to new opportunities for using anti-inflammatory strategies to correct the metabolic consequences of excess adiposity. Molecular pathways linking inflammation and insulin resistance include the activation of JNK and IKKβ/NF-κB, which promote insulin resistance through various mechanisms. Proinflammatory cytokines such as TNF-α, IL-6, and resistin, produced by adipocytes and macrophages, activate these pathways. Inflammation is also closely linked to the pathogenesis of atherosclerosis, suggesting that it might be a common denominator linking obesity to its pathological sequelae. The liver and skeletal muscle are other major sites of insulin resistance in obesity and T2D. While inflammation is activated in the liver and skeletal muscle, it does not appear to be a primary site of initiation. Instead, these tissues are targets of inflammation-induced insulin resistance. Future trials to target inflammation include evaluating the efficacy of anti-inflammatory drugs such as high-dose salicylates, specific JNK or IKKβ inhibitors, and compounds that block TNF-α, IL-6, TLR, or chemokine signaling. These approaches may provide clinical benefits to a large number of persons affected by the obesity epidemic and related metabolic disorders.