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Abstract Organisms are experiencing higher average temperatures and greater temperature variability because of anthropogenic climate change. Some populations respond to changes in temperature by shifting their ranges or adjusting their phenotypes via plasticity and/or evolution, while others go extinct. Predicting how populations will respond to temperature changes is challenging because extreme and unpredictable climate changes will exert novel selective pressures. For this reason, there is a need to understand the physiological mechanisms that regulate organismal responses to temperature changes. In vertebrates, glucocorticoid hormones mediate physiological and behavioral responses to environmental stressors and thus are likely to play an important role in how vertebrates respond to global temperature changes. Glucocorticoids have cascading effects that influence the phenotype and fitness of individuals, and some of these effects can be transmitted to offspring via trans- or intergenerational effects. Consequently, glucocorticoid-mediated responses could affect populations and could even be a powerful driver of rapid evolutionary change. Here, we present a conceptual framework that outlines how temperature changes due to global climate change could affect population persistence via glucocorticoid responses within and across generations (via epigenetic modifications). We briefly review glucocorticoid physiology, the interactions between environmental temperatures and glucocorticoid responses, and the phenotypic consequences of glucocorticoid responses within and across generations. We then discuss possible hypotheses for how glucocorticoid-mediated phenotypic effects might impact fitness and population persistence via evolutionary change. Finally, we pose pressing questions to guide future research. Understanding the physiological mechanisms that underpin the responses of vertebrates to elevated temperatures will help predict population-level responses to the changing climates we are experiencing.