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The northeastern Pacific Ocean is undergoing changes in temperature, carbonate chemistry, and dissolved oxygen concentration in concert with global change. Each of these stressors has wide-ranging effects on physiological systems, which may differ among species and life-history stages. Simultaneous exposure to multiple stressors may lead to even stronger impacts on organisms, but interacting effects remain poorly understood. Here, we examine how single- and multiple-stressor effects on physiology may drive changes in the behavior, biogeography, and ecosystem structure in coastal marine ecosystems, with emphasis on the California Current Large Marine Ecosystem. By analyzing the effects of stressors on physiological processes common to many marine taxa, we may be able to develop broadly applicable understandings of the effects of global change. This mechanistic foundation may contribute to the development of models and other decision-support tools to assist resource managers and policymakers in anticipating and addressing global change–driven alterations in marine populations and ecosystems.