Globally, coral reefs are more at risk to human-induced stressors – such as climate change, including ocean warming, acidification, and altered water quality due to coastal development – now, than at any other time in recorded history. Dramatic effects on fish performance, distribution, and overall ecosystem health are predicted. While the success of the fishes over their long evolutionary history is thought to have hinged on key adaptations for maintaining oxygen transport and physiological performance under challenging conditions, whether they possess the necessary plasticity and/or adaptations to keep pace with the large-scale, rapid changes plaguing their habitats today is not known. Moreover, the coral reef fishes – in particular – diversified more recently on the geological time scale, with most species radiating within the last 23 million years, a period characterised by relatively stable environmental conditions. Evolving and existing under stable environmental conditions may heighten the vulnerability of coral reef fishes to the rapidly changing conditions coral reefs are facing today. By harnessing geographic gradients, such as the latitudinal thermal profile along the Great Barrier Reef, and local extreme environments, such as the volcanic CO2 seeps in the reefs of Papua New Guinea, as analogues for future change and integrating physiological, biochemical, and molecular techniques, the mechanisms that fish use to acclimate and adapt to these stressors can be identified. Such responses may become potential targets of natural selection and will determine which species and populations may be most at risk from climate change and other human-induced stressors and potentially priorities for conservation and management.