The cJun NH₂-terminal kinase isoform JNK1 is implicated in the mechanism of obesity-induced insulin resistance. Feeding a high-fat diet causes activation of the JNK1 signaling pathway, insulin resistance, and obesity in mice. Germ-line ablation of Jnk1 prevents both diet-induced obesity and insulin resistance. Genetic analysis indicates that the effects of JNK1 on insulin resistance can be separated from effects of JNK1 on obesity. Emerging research indicates that JNK1 plays multiple roles in the regulation of insulin resistance, including altered gene expression, hormone/cytokine production, and lipid metabolism. Together, these studies establish JNK1 as a potential pharmacological target for the development of drugs that might be useful for the treatment of insulin resistance, metabolic syndrome, and type 2 diabetes.