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The human body is continuously exposed to a wide variety of physical, chemical, and biological stress stimuli from both the external and internal environments. In order to adapt to or resist stress, cells are equipped with multiple signaling systems, which elicit a wide range of stress responses. Stress signaling also operates to eliminate cells with severe stress-induced damage through the induction of apoptosis. Once stress signaling is compromised in certain adverse conditions, however, cells exhibit aberrant responses to stress, which can eventually cause various diseases including cancer. In the present review, the authors focus on the current understanding of the critical linkage between stress signaling and cancer. (Cancer Sci 2007; 98: 1521–1527)