JNKs (c-jun NH2-terminal kinases) are members of the MAP kinase family1 that are primarily activated by cytokines and exposure to environmental stress.2,3 JNKs are serine/threonine kinases that are able to phosphorylate the N-terminal transactivation domain of c-Jun, resulting in enhancement of c-Jun dependent transcriptional events. Human JNKs are encoded by three genes, Jnk1, Jnk2, and Jnk3,2,4-6 and they are derived from 10 splice variants.7 JNK1 and JNK2 are ubiquitously expressed, whereas JNK3 has much more limited expression, primarily confined to the nervous system with low level of expression in the heart and testes.6 JNK1, JNK2, and JNK3 knockout mice develop normally; however, dual JNK1 and JNK2 mice die prematurely and exhibit abnormalities attributed to apoptosis.8,9 The signaling network of JNKs is not well understood and continuously evolving.10 JNKs are activated by MKK4 and MKK7, and activation of MKKs is performed by a large number of kinases including ASK1, TAK1, MLKs, and MAPKKKs such as Tpl2. JNKs are deactivated by MAP kinase phosphatases including MKP1 and MKP5. Scaffolding proteins that assemble the molecules of the JNK pathway, termed JIP (Jnk interacting proteins), are involved in mediating the stimulus and compartment specific signals. Nuclear translocation of JNK leads to the phosphorylation of a number of transcription factors, most notably the c-Jun component of AP-1. JNKs act at several points in the apoptosis cascade interacting with antiapoptotic proteins Bcl-2, Bcl-xL, and Mcl-1 and proapoptotic proteins Bim, Bmf, and Bad, thus triggering the mitochondrial cell death machinery (Figure 1). An emerging role of JNK in endoplasmic reticulum (ER) stress via IRE-1 involving TNF-receptor associated factor 2 links JNK signaling with metabolic syndrome.11,12 The central role of JNK in many physiological processes makes it an interesting target, thus providing multiple opportunities for the design of small molecule inhibitors that might modulate specific components of JNK signaling. The growing list of diseases where interfering with JNK mediated signaling may play an important role is summarized in the following sections.