Thermal histories are modeled from new apatite (U-Th)/He and apatite fission-track data in order to quantitatively constrain the landscape evolution of the Grand Canyon region. Fifty new samples and their associated thermochronometric ages are presented here. Samples span from Lee’s Ferry in the east to Quartermaster Canyon in the west and include four age-elevation transects into Grand Canyon and borehole samples from the Coconino Plateau. Twenty-seven samples are inversely modeled to provide continuous thermal histories. This represents the most extensive and complete dataset on patterns of long-term exhumation in the Grand Canyon region, and it enables us to constrain the timing and magnitude of erosion and also discriminate between canyon incision and broader planation. The new data suggest that the early Cenozoic landscape in eastern Grand Canyon was low in relief and does not indicate the presence of an early Cenozoic precursor to the modern Grand Canyon. However, there is evidence for the incision of a smaller-scale canyon across the Kaibab Uplift at 28–20 Ma. This middle-Cenozoic denudation event was accompanied by the removal of a majority of remaining Mesozoic strata west of the Kaibab Uplift. In contrast, just upstream in the area of Lee’s Ferry, ∼2 km of Mesozoic strata remained over the middle Cenozoic and were removed after 10 Ma.