Mammalian cells respond to extracellular stimuli by activating signaling cascades that are mediated by members of the MAP kinase family. MAP kinases act by phosphorylating various substrates including transcription factors. These in turn regulate expression of specific sets of genes and thus can mediate a specific genetic response to the stimulus. The basic organization of signaling pathways leading to MAP kinase activation is highly conserved from yeast to mammalian cells. Several subgroups of MAP kinases were identified in mammalian cells, which differ in their substrate specificities and regulation. Members of the JNK subgroup of MAP kinases are activated in response to diverse extracellular stimuli, including UV irradiation, proinflammatory cytokines and certain mitogens. The JNKs phosphorylate specific sites on the amino terminal trans-activation domain of transcription factor c-Jun, an important component of transcriptional activator AP-1. Phosphorylation of these sites stimulates the ability of c-Jun to activate transcription of specific target genes. In addition to c-Jun, the JNKs phosphorylate and activate several other transcription factors, most of which can contribute to AP-1 activity. This review provides an overview of MAP kinase activation, with particular emphasis on the signal transduction pathways leading to activation of the JNK subgroup of MAP kinases. We also discuss the regulation of AP-1 activity by JNK and other MAP Kinases, as well as the possible functions of JNK activation. In order to survive and develop normally, eukaryotic cells must be able to respond to a diverse array of extracellular stimuli and adapt to adverse conditions. In many cases cells respond to extracellular stimuli and environmental stresses by adjusting their responses to other stimuli, and by adjusting their gene expression programs. Exposure to certain extracellular stimuli can trigger cell growth and division, while exposure to other stimuli can induce cell differentiation or even programmed cell death. Exposure to environmental stresses results in activation of various stress responses which help the cells withstand adverse environmental conditions. An intriguing question is how external stimuli that signal through cell surface receptors, elicit changes in cell phenotype and morphology. One common way for executing such responses is by turning on cascades of biochemical events in response to receptor activation which transmit information from the cell surface to the transcriptional machinery in the nucleus. By modulating the activities of sequence specific transcription factors and combinations thereof, extracellular stimuli activate or repress the expression of specific sets of genes. The products of such genes are the ultimate mediators of the phenotypic responses. It is important to elucidate the components of these signal transduction pathways and the mechanisms that govern the transmission of information. In addition to understanding how normal cells respond to extracellular stimuli, such information will help in deciphering what goes wrong in a variety of clinical disorders. In diseases such as cancer or diabetes, for example, cells fail to respond properly to extracellular stimuli, resulting in loss of normal growth control or improper regulation of energy metabolism. Among the major types of signal transduction pathways in eukaryotic cells are protein kinase cascades which culminate in activation of a family of protein kinases known as mitogen activated protein w x kinases, or MAP kinases 1–4. Although they vary in their substrate specificities and responses to extracellular stimuli, MAP kinases are highly conserved in Ž their primary structure and mode of activation see