The end Pleistocene to early Holocene drying of the North American midcontinent is an important case study for understanding regional drought, its drivers, and its impacts. This paper synthesizes pollen, δ13C, eolian, and paleohydrological proxies to document the spatial and temporal patterns in the onset and rate of drying. The timing of onset ranged from 14 to 6 ka with most sites drying between 10 and 8 ka (calendar years ago). The dominant spatial pattern is time transgressive, with interior Great Plains sites beginning to dry before peripheral sites. This time-transgressive trend can be explained as a region-wide drying that caused ecotones to shift eastward, or could indicate a progressive shift in atmospheric drying from west to east. One-third of sites responded rapidly to drying; a cluster of rapid responses occurred ca. 8 ka. The combination of onsets between 14 and 6 ka and rapid responses at 8 ka strongly suggests that (1) the combination of high summer insolation, Laurentide Ice Sheet retreat, and Lake Agassiz drainage drove midcontinental drying, and (2) drying accelerated with Laurentide Ice Sheet collapse at 8.4 ka. Local factors strongly mediate the timing and rate of site responses to regional drying. Local responses to future drying in the Great Plains also should be highly variable, which challenges impact assessments of future climate changes.