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The eastern Mediterranean region witnessed changes in human culture of the highest importance between similar to 9000 and similar to 2500 cal. BP (7000-500 BC) and over the same time period was affected by very significant shifts in climate. Stable isotope data from lake and deep-sea sediment cores and from cave speleothems show an overall trend from a wetter to a drier climate during the mid Holocene. Superimposed on this trend were multicentennial oscillations in climate, with notable arid phases occurring around 5300-5000 BP, 4500-3900 BP, and 3100-2800 BP (all ages are expressed in calibrated/calendar years). These phases coincide with major archaeological transitions across the eastern Mediterranean region (Chalcolithic to early Bronze Age, EBA to MBA, and LBA to Iron Age) implying that environmental stress or opportunity may have acted as a pacemaker for cultural change and reorganisation. We use C-14 and delta C-13 analysis of archaeobotanical samples from two protohistoric sites in Syria to illustrate the linkage between water availability, climate and cultural change during the third and second millennia BC. Specific societal responses to environmental change were not predictable in advance, but resulted instead from contingent processes involving antecedent conditions, human choice and adaptive strategies. Pollen analysis highlights how changes in climate were coupled to increasing human impacts to transform the region’s landscapes. Initial human-induced land-cover transformation commonly took place during Bronze Age times, sometimes coinciding with phases of drier climate, although the pattern and precise timing varied between sites. Changes in climate between the early and late Holocene thus helped to transform eastern Mediterranean landscape ecologies and human cultures, but in complex, non-deterministic ways.