Environmental stimuli elicit a stress response, which helps to maintain cell survival. In budding yeast Saccharomyces cerevisiae, environmental cues can activate calcineurin, a highly conserved Ca2+- and calmodulin-dependent protein phosphatase. Calcineurin dephosphorylates the transcription factor Crz1, leading to accumulation of Crz1 in the nuclei and expression of stress responsive genes under the control of a calcineurin-dependent response element (CDRE). Ethanol is the final product of sugar fermentation by yeast, and thus a frequently encountered yeast stressor. However, adaptation of yeast to ethanol stress is poorly understood. In this study, we show that ethanol stimulates calcineurin-dependent nuclear localization of Crz1 and CDRE-dependent gene expression. Moreover, cells in which CRZ1 is deleted exhibit defective adaptation to ethanol stress, while a multicopy plasmid of CRZ1 confers an increased level of adaptive stress tolerance to ethanol. Taken together, the results indicate that ethanol activates the calcineurin/Crz1 pathway and that CRZ1 is crucial for cell survival under ethanol-induced stress. (C) 2008, The Society for Biotechnology, Japan. All rights reserved.