It is generally agreed that a region encompassing the Colorado Plateau has been uplifted by sub-crustal processes. Admittance calculations, tomographic studies and receiver function analyses suggest that dynamic support is generated by some combination of convective upwelling and lithospheric thickness changes. Notwithstanding advances in our understanding of present-day setting, uplift rate histories are poorly constrained and debated: an improved history will aid discrimination between proposed models. Here, we show that a regional uplift rate history can be obtained by inverting longitudinal river profiles. We assume that the shape of a river profile is controlled by uplift rate and moderated by erosion. In our model, uplift rate is allowed to vary smoothly as a function of space and time, upstream drainage area is invariant with time. Simultaneous inversion of river profiles from the Colorado, Rio Grande, Columbia and Mississippi catchments shows that three phases of regional uplift occurred. The first phase occurred between 80 and 50 Myrs, when ∼1 km of uplift was generated at a rate of ∼0.03 mm/yr. A second phase occurred between 35 and 15 Myrs, when ∼1.5 km of uplift was generated at a faster rate of ∼0.06 mm/yr. A final phase of uplift commenced ∼5 Myrs ago. These distinct phases of Late Cretaceous and Oligocene uplift are corroborated by stratigraphic considerations, by thermochronometric data, and by stratigraphic evidence of periodic clastic efflux delivered into the Gulf of Mexico. An episodic uplift history is consistent with staged removal of thick lithospheric mantle beneath a large region, which is currently centered on Yellowstone.