Sky islands are unique geologic formations, home to populations of organisms that have weathered climate change since the Pleistocene. Long-term isolation and climatic differences between sky islands and adjacent mountain chains result in natural laboratories well suited for examining the direct effects of climate change. Here, we review the global sky island literature to examine how taxa have responded to climate change. Results show lineage formation, reduced genetic variation, and trait evolution across taxa driven by genetic drift and natural selection. These effects continue today due to ongoing habitat reduction and steep selective gradients on sky islands relative to mountain chains. Comparative studies and experimental manipulations are needed to build broad inference into how past climate change has shaped the structure and function of whole ecosystems. The next era of sky island research is poised to create a model for climate change responses and eco-evolutionary dynamics, with profound conservation implications. Expected final online publication date for the Annual Review of Ecology, Evolution, and Systematics, Volume 54 is November 2023. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.