Over the past 10 Ma, the high-relief landscapes of the Colorado Plateau–southern Rocky Mountains region have been shaped by erosional processes. Incision rates have increased in the southern Rocky Mountains, the Colorado River system has been superimposed across buried Laramide structures as it was integrated from the Rocky Mountains to the Gulf of California, the modern Grand Canyon formed, and there has been widespread denudation of the Canyonlands region of the Colorado Plateau. We examine the spatial and temporal distribution of erosion and its associated isostatic rebound since 10 Ma. Erosion estimates come from apatite fission track (AFT) and apatite (U-Th)/He (AHe) thermochronometric studies at 14 sites across the region, including recent AHe data with ages younger than 12 Ma, and from ca. 10 Ma 40 Ar/ 39 Ar dated basalt paleosurfaces at 55 locations on the perimeter of the Colorado Plateau and in the southern Rocky Mountains. Estimated eroded thickness is added to modern topography above numerous control points to reconstruct a 10 Ma paleosurface across the region (referenced to modern elevations); this also yields an eroded thickness volume. Erosion has been spatially variable since 10 Ma: we find widespread denudation with as much as 2 km of incision along rivers in the Canyonlands region of Utah, 1–1.5 km of incision along rivers exiting the Rocky Mountains onto the eastern piedmont since 6 Ma, ∼1 km removed across the high peaks of the southern Rocky Mountains since 10 Ma, and little net erosion in the Basin and Range. Post–10 Ma flexural isostatic response to the eroded volume is calculated using known variable elastic thickness. This rebound caused much of the Colorado Plateau region to undergo more than 800 m of rock uplift, exceeding 1 km in local areas in the Canyonlands and southwestern Colorado. The Lees Ferry and Glen Canyon areas have been isostatically uplifted >500 m relative to the eastern Grand Canyon and the Tavaputs Plateau has been isostatically uplifted 400 m relative to Browns Park. This differential rock uplift driven by erosional isostasy has created or accentuated many of the features of the modern landscape. This component of rock uplift is “removed” by adding the eroded thickness onto modern topography, then subtracting the calculated rebound. The resulting (pre-erosion and pre-rebound) map provides a model of the 10 Ma landscape, neglecting any tectonic uplift contribution to regional elevations. This model suggests the presence of internal drainages on the Colorado Plateau, that the elevation of the Green River Basin and the Tavaputs Plateau were subequivalent, allowing the Green River to flow southward, and shows high topography in the Rocky Mountains that mimicked modern topography, but with potentially lower relief. Future refinements of both the timing and magnitude of differential erosion and rebound models provide an avenue for improved models for Cenozoic landscape evolution of the region. This paper is an advance over previous studies that focused just on the Colorado Plateau. Here we evaluate isostatic response to erosion in an extended region that includes parts of the Basin and Range, Colorado Plateau, southern Rocky Mountains, and eastern piedmont of the Rocky Mountains. We find that erosion of the southern Rocky Mountains and eastern piedmont is comparable to that of the Colorado Plateau and that the flexural isostatic rebounds of all these regions are coupled and cannot be considered in isolation. Furthermore, we focus on the 10 Ma time frame, rather than the 30 or 70 Ma period of previous researchers, as the key time frame during which the modern landscape rapidly evolved. In addition, the use of AFT and AHe thermochronometric constraints on thicknesses and ages of now-eroded sediments has solved key problems that hampered previous erosion studies. Data and analyses of regional post–10 Ma differential erosion and its resulting differential isostatic rebound provide essential constraints for any viable models for landscape evolution in this classic region.