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 p38 MAP kinases are preferentially activated by environmental stresses and are actively involved in various stress responses including cell death, survivaland differentia tion. Apoptosis signal-regulating kinase 1 (ASK1)-a serine/threonine protein kinase-is a member of the MAPKKK family and activates both JNK and p38 path ways. It is well known that ASK! is activated in cells treated with death receptor lig ands and oxidant stress, such as that causedby hydrogen peroxide(H202). Moreover, recent studies have revealed new mechanisms by which ASK! is activated in response to various types of extracellular and intracellular signals, such as endoplas mic reticulum(ER) stress, calcium signaling, and G-protein coupled receptor(GPCR) signaling. This review summarizes the regulatory mechanisms of ASK! activity and the physiological roles of ASK1-mediated signal transduction.