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The Colorado Plateau is located in the interior, dry end of two moisture trajectories coming from opposite directions, which have made this region a target for unusual climate fluctuations. A multi-decadal drought event some 850 years ago may have eliminated maize cultivation by the first human settlers of the Colorado Plateau, the Fremont and Anasazi people, and contributed to the abandonment of their settlements. Even today, ranching and farming are vulnerable to drought and struggle to persist. The recent use of the Colorado Plateau primarily as rangeland has made this region less tolerant to drought due to unprecedented levels of surface disturbances that destroy biological crusts, reduce soil carbon and nitrogen stocks, and increase rates of soil erosion. The most recent drought of 2002 demonstrated the vulnerability of the Colorado Plateau in its currently depleted state and the associated costs to the local economies. New climate predictions for the southwestern United States include the possibility of a long-term shift to warmer, more arid conditions, punctuated by megadroughts not seen since medieval times. It remains to be seen whether the present-day extractive industries, aided by external subsidies, can persist in a climate regime that apparently exceeded the adaptive capacities of the Colorado Plateau’s prehistoric agriculturalists.