Recently the Southwest has experienced a spate of dryness, which presents a challenge to the sustainability of current water use by human and natural systems in the region. In the Colorado River Basin, the early 21st century drought has been the most extreme in over a century of Colorado River flows, and might occur in any given century with probability of only 60%. However, hydrological model runs from downscaled Intergovernmental Panel on Climate Change Fourth Assessment climate change simulations suggest that the region is likely to become drier and experience more severe droughts than this. In the latter half of the 21st century the models produced considerably greater drought activity, particularly in the Colorado River Basin, as judged from soil moisture anomalies and other hydrological measures. As in the historical record, most of the simulated extreme droughts build up and persist over many years. Durations of depleted soil moisture over the historical record ranged from 4 to 10 years, but in the 21st century simulations, some of the dry events persisted for 12 years or more. Summers during the observed early 21st century drought were remarkably warm, a feature also evident in many simulated droughts of the 21st century. These severe future droughts are aggravated by enhanced, globally warmed temperatures that reduce spring snowpack and late spring and summer soil moisture. As the climate continues to warm and soil moisture deficits accumulate beyond historical levels, the model simulations suggest that sustaining water supplies in parts of the Southwest will be a challenge.