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For decades, multiple anthropogenic stressors have threatened the Galápagos Islands. Widespread marine pollution such as oil spills, persistent organic pollutants, metals, and ocean plastic pollution has been linked to concerning changes in the ecophysiology and health of Galápagos species. Simultaneously, illegal, unreported, and unregulated fishing are reshaping the composition and structure of endemic and native Galápagos pelagic communities. In this novel review, we discuss the impact of anthropogenic pollutants and their associated ecotoxicological implications for Galápagos species in the face of climate change stressors. We emphasize the importance of considering fishing pressure and marine pollution, in combination with climate-change impacts, when assessing the evolutionary fitness of species inhabiting the Galápagos. For example, the survival of endemic marine iguanas has been negatively affected by organic hydrocarbons introduced via oil spills, and endangered Galápagos sea lions exhibit detectable concentrations of DDT, triggering potential feminization effects and compromising the species' survival. During periods of ocean warming (El Niño events) when endemic species undergo nutritional stress, climate change may increase the vulnerability of these species to the impacts of pollutants, resulting in the species reaching its population tipping point. Marine plastics are emerging as a deleterious and widespread threat to endemic species. The Galápagos is treasured for its historical significance and its unparalleled living laboratory and display of evolutionary processes; however, this unique and iconic paradise will remain in jeopardy until multidisciplinary and comprehensive preventative management plans are put in place to mitigate and eliminate the effects of anthropogenic stressors facing the islands today. We present a critical analysis and synthesis of anthropogenic stressors with some progress from local and international institutional efforts and call to action more precautionary measures along with new management philosophies focused on understanding the processes of change through research to champion the conservation of the Galápagos. Integr Environ Assess Manag 2023;19:870-895. © 2022 SETAC., (© 2022 SETAC.)