Inflammation is thought to underlie the pathogenesis of many chronic diseases. It is now established that obesity results in a state of chronic low‐grade inflammation thought to contribute to several metabolic disorders' including insulin resistance and pancreatic islet dysfunction. The protein kinases JNK1 and IKKβ have been found to serve as critical molecular links between obesity, metabolic inflammation, and disorders of glucose homeostasis. The precise mechanisms of these linkages are still being investigated. However, as we discuss here, JNK1 and IKKβ are activated by almost all forms of metabolic stress that have been implicated in insulin resistance or islet dysfunction. Furthermore, both JNK1 and IKKβ are critically involved in the promotion of diet‐induced obesity, metabolic inflammation, insulin resistance, and β‐cell dysfunction. Understanding the molecular mechanisms by which JNK1 and IKKβ mediate obesity‐induced metabolic stress is likely to be of importance for the development of new treatments for a variety of obesity‐associated diseases.—Solinas, G., Karin, M. JNK1 and IKKβ: molecular links between obesity and metabolic dysfunction. FASEB J. 24, 2596–2611 (2010). www.fasebj.org