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The long-term response of ancient societies to climate change has been a matter of global debate. Until recently, the lack of integrative studies using archaeological, palaeoecological and palaeoclimatological data prevented an evaluation of the relationship between climate change, distinct subsistence strategies and cultural transformations across the largest rainforest of the world, Amazonia. Here we review the most relevant cultural changes seen in the archaeological record of six different regions within Greater Amazonia during late pre-Columbian times. We compare the chronology of those cultural transitions with high-resolution regional palaeoclimate proxies, showing that, while some societies faced major reorganization during periods of climate change, others were unaffected and even flourished. We propose that societies with intensive, specialized land-use systems were vulnerable to transient climate change. In contrast, land-use systems that relied primarily on polyculture agroforestry, resulting in the formation of enriched forests and fertile Amazonian dark earth in the long term, were more resilient to climate change.