© 2017. American Geophysical Union. All Rights Reserved. A multidisciplinary approach is used to analyze the Cenozoic uplift history of South America. Residual depth anomalies of oceanic crust abutting this continent help to determine the pattern of present-day dynamic topography. Admittance analysis and crustal thickness measurements indicate that the elastic thickness of the Borborema and Altiplano regions is ≤10 km with evidence for sub-plate support at longer wavelengths. A drainage inventory of 1827 river profiles is assembled and used to investigate landscape development. Linear inverse modeling enables river profiles to be fitted as a function of the spatial and temporal history of regional uplift. Erosional parameters are calibrated using observations from the Borborema Plateau and tested against continent-wide stratigraphic and thermochronologic constraints. Our results predict that two phases of regional uplift of the Altiplano plateau occurred in Neogene times. Regional uplift of the southern Patagonian Andes also appears to have occurred in Early Miocene times. The consistency between observed and predicted histories for the Borborema, Altiplano, and Patagonian plateaux implies that drainage networks record coherent signals that are amenable to simple modeling strategies. Finally, the predicted pattern of incision across the Amazon catchment constrains solid sedimentary flux at the Foz do Amazonas. Observed and calculated flux estimates match, suggesting that erosion and deposition were triggered by regional Andean uplift during Miocene times.