Mammalian cells are frequently exposed to a variety of environmental stresses, such as ultraviolet rays, ionizing radiation, genotoxins, heat shock, and oxidative stress. In coping with the barrage of these and other stresses, multi-cellular eukaryotic organisms have developed a strategy as to how damaged cells will respond to stresses. In general, if the intensity of the damage is moderate, the cell will seek to repair the damage. If, however, the damage to a cell is too severe to be repaired, the affected cells are eliminated by apoptosis. This cell death reduces the risk to the organism as a whole, such as development of a cancer. Such a crucial decision between survival and death is, at least in part, mediated by the stress-activated MAP kinase (SAPK) pathways. SAPKs are a group of serine/threonine protein kinases that convert extracellular stress stimuli into diverse cellular responses, including cell cycle arrest, apoptotic cell death, and cytokine production, through phosphorylation of specific target proteins. Recent progress in the identification of molecules that participate in the SAPK pathways, such as GADD45 proteins and Wipl, has provided new insights, not only into the molecular basis of the cellular response to environmental stress, but also into the etiology of human diseases including cancer.