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, 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 p38 pathways. 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.