Recently published thermochronological and paleoelevation studies in the Grand Canyon region, combined with sedimentary provenance data in both the coastal and interior portions of the North American Cordillera, place important new constraints on the paleohydrological evolution of the southwestern United States. Review and synthesis of these data lead to an interpretation where incision of a large canyon from a plain of low elevation and relief to a canyon of roughly the length and depth of modern Grand Canyon occurred primarily in Campanian time (80–70 Ma). Incision was accomplished by a main-stem, NE-flowing antecedent river with headwaters on the NE slope of the North American Cordillera in California, referred to herein after its source region as the California River. At this time, the river had cut to within a few hundred meters of its modern erosion level in western Grand Canyon, and to the level of Lower Mesozoic strata in eastern Grand Canyon. Subsequent collapse of the headwaters region into a continental borderland and coeval uplift of the Cordilleran foreland during the Laramide orogeny reversed the river's course by Paleogene time. After reversal, its terminus lay near its former source regions in what is now the Western Transverse Ranges and Salinian terrane. Its headwaters lay in the ancient Mojave/Mogollon Highlands region of Arizona and eastern California, apparently reaching as far northeast as the eastern Grand Canyon region. This system is herein referred to after its source region as the Arizona River. From Paleogene through late Miocene time, the interior of the Colorado Plateau was a closed basin separated from the Arizona River drainage by an asymmetrical divide in the Lees Ferry–Glen Canyon area, with a steep SW flank and gently sloping NE flank that drained into large interior lakes, fed primarily by Cordilleran/Rocky Mountain sources to the north and west, and by recycled California River detritus shed from Laramide uplifts on the plateau. By Oligocene time, the lakes had largely dried up and were replaced by ergs. By mid-Miocene time, a pulse of unroofing had lowered the erosion level of eastern Grand Canyon to within a few hundred meters of its present level, and the Arizona River drainage below modern Grand Canyon was deranged by extensional tectonism, cutting off the supply of interior detritus to the coast. Increasing moisture in the Rocky Mountains in late Miocene time reinvigorated fluviolacustrine aggradation NE of the asymmetrical divide, which was finally overtopped between 6 and 5 Ma, lowering base level in the interior of the plateau by 1500 m. This event reintegrated the former Arizona drainage system through a cascade of spillover events through Basin and Range valleys, for the first time connecting sediment sources in Colorado with the coast. This event, combined with the intensification of summer rainfall as the Gulf of California opened, increased the sediment yield through Grand Canyon by perhaps two orders of magnitude from its Miocene nadir, giving birth to the modern subcontinental-scale Colorado River drainage system. The Colorado River has thus played a major role in unroofing the interior of the Colorado Plateau, but was not an important factor in the excavation of Grand Canyon.