The correspondence between seismic velocity anomalies in the crust and mantle and the differential incision of the continental-scale Colorado River system suggests that significant mantle-to-surface interactions can take place deep within continental interiors. The Colorado Rocky Mountain region exhibits low-seismic-velocity crust and mantle associated with atypically high (and rough) topography, steep normalized river segments, and areas of greatest differential river incision. Thermochronologic and geologic data show that regional exhumation accelerated starting ca. 6–10 Ma, especially in regions underlain by low-velocity mantle. Integration and synthesis of diverse geologic and geophysical data sets support the provocative hypothesis that Neogene mantle convection has driven long-wavelength surface deformation and tilting over the past 10 Ma. Attendant surface uplift on the order of 500–1000 m may account for ∼25%–50% of the current elevation of the region, with the rest achieved during Laramide and mid-Tertiary uplift episodes. This hypothesis highlights the importance of continued multidisciplinary tests of the nature and magnitude of surface responses to mantle dynamics in intraplate settings.