Molecular cloning has identified three genes encoding multiple stress-activated protein kinase (JNK/SAPKs) isoforms and splice variants, that are widely distributed in mammalian tissues, being the β isoform the most abundant in brain. These proteins are important components of the JNK/SAPK cascade, which is activated by a variety of stress stimuli (heat, UV radiation, oxidative stress), the cytokines interleukin-1 (IL-1) and tumor necrosis factor α (TNFα) and by certain hormones and neurotransmitters. The target substrates of JNK/SAPKs include diverse transcription factors (c-Jun) and other proteins (tau). Therefore, the JNK/SAPK cascade represents a central component of many signal transduction pathways that modulate gene expression in response to extracellular stimuli. The JNK/SAPK cascade is also activated in some characteristic pathological conditions (glutamate excitotoxicity, apoptosis, oxidative damage) found in the neurodegenerative diseases.