The cJun NH2-terminal kinase (JNK) signaling pathway is implicated in the pathogenesis of diabetes and cancer. High fat diet-induced obesity causes activation of JNK in target tissues. JNK-deficient mice are resistant to the effects of feeding a high fat diet, including protection against insulin resistance and failure of obesity development. We have used tissue-specific JNK-deficient mice to probe the mechanism of JNK regulation of insulin resistance and obesity. We show that JNK plays different roles in multiple tissues and that the phenotype of whole body JNK-deficient mice reflects the interactions between these different JNK-dependent processes. The molecular mechanisms of JNK function in metabolic disease and cancer will be discussed.