An overview of the archaeological data produced over the last decades for Brazil, coupled with a background of recent paleoenvironmental studies, suggests that during the mid-Holocene vast areas of Central Brazil ceased to be occupied by human groups. Independent data from dated human skeletons, rock-shelter stratigraphy, and chronology of open-air sites converge to support the inference that these areas were depopulated or altogether abandoned. Paleoenvironmental data suggest that dryness events constitute the major cause behind the observed trends. This phenomenon expands the already perceived notion that climatic stresses had a major role in the shaping of human settlement patterns in marginal environments, such as deserts and high-altitude settings.