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This article highlights issues and presents strategies for conducting intervention research in highly unstable environments such as schools, critical care units, and long‐term care facilities. The authors draw on their own experiences to discuss the challenges that may be encountered in highly unstable settings. The concept of validity provides a framework for understanding the value of addressing the many methodological issues that can emerge in settings characterized by instability. We explain unstable environments by elaborating on knowable elements that contribute to instability. Strategies are provided for improving success of intervention research in unstable settings by carrying out an environmental assessment prior to beginning a study. © 2008 Wiley Periodicals, Inc. Res Nurs Health 32:110–121, 2009