The mitogen-activated protein (MAP) kinase cascades play essential roles in a variety of cell processes by influencing transcriptional or translational regulation. ERKs play a central role in survival and mitogenic signaling, while JNKs and p 38 MAP kinases are preferentially activated by environmental stresses and are actively involved in various stress responses including cell death, survival and differentiation. Apoptosis signal-regulating kinase 1 (ASK1)-a serine/threonine protein kinase-is a member of the MAPKKK family and activates both JNK and p 38 path-ways. It is well known that ASK1 is activated in cells treated with death receptor ligands and oxidant stress, such as that caused by hydrogen peroxide (H₂O₂). Moreover, recent studies have revealed new mechanisms by which ASK1 is activated in response to various types of extracellular and intracellular signals, such as endoplasmic reticulum (ER) stress, calcium signaling, and G-protein coupled receptor (GPCR) signaling. This review summarizes the regulatory mechanisms of ASK1 activity and the physiological roles of ASK1-mediated signal transduction.

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