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 elasticthickness of the Borborema and Altiplano regions is  10 km with evidence for sub-plate support at longerwavelengths. A drainage inventory of 1827 river profiles is assembled and used to investigate landscapedevelopment. Linear inverse modeling enables river profiles to be fitted as a function of the spatial and tem-poral history of regional uplift. Erosional parameters are calibrated using observations from the BorboremaPlateau and tested against continent-wide stratigraphic and thermochronologic constraints. Our results pre-dict that two phases of regional uplift of the Altiplano plateau occurred in Neogene times. Regional uplift ofthe southern Patagonian Andes also appears to have occurred in Early Miocene times. The consistencybetween observed and predicted histories for the Borborema, Altiplano, and Patagonian plateaux impliesthat 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 Fozdo Amazonas. Observed and calculated flux estimates match, suggesting that erosion and deposition weretriggered by regional Andean uplift during Miocene times.