Sedimentary basins of western South America are sensitive to the evolution of topography and sediment source regions, making them well suited to address issues of Andean uplift, provenance, and paleodrainage. Integration of regional stratigraphic relationships with data on sediment accumulation, provenance, and deformation timing enables a reconstruction of subduction-related Mesozoic-Cenozoic mountain building. The basins evolved in diverse structural settings on both flanks of the long-lived Andean magmatic arc, with strong signatures of retroarc crustal shortening, flexure, and rapid accumulation in foreland and hinterland basins. Extension intermittently affected the region, with regional pre-Andean Late Triassic–Early Cretaceous backarc subsidence, then later local Andean subsidence in selected forearc, arc, and retroarc zones during Late Cretaceous-Cenozoic orogenesis. The principal sediment sources—the craton, magmatic arc, and retroarc fold-thrust belt—are distinguishable through provenance studies, particularly detrital zircon U-Pb geochronology, which defines major transitions in topography and drainage patterns. The inception of Andean shortening and probable establishment of a single contiguous topographic barrier are expressed in retroarc regions by rapid flexural subsidence and a reversal in sediment polarity from cratonic to Andean sources. This pivotal transition from a westward (Pacific) draining pre-Andean landscape to an eastward (Atlantic) draining Andean landscape is fundamental to species distributions, separation events, and biodiversification. An enigmatic Paleogene hiatus in the foreland succession reflected by reduced accumulation and/or regional unconformities attests to a period of diminished shortening, or neutral to extensional conditions. Such fluctuations in tectonic regime may have profound consequences for the regulation of topography, with modification and possibly local erasure of the Andean topographic divide. A renewed emphasis on such hiatuses (their spatial extent, age, and origin) along with regional cross-orogen comparisons of forearc versus retroarc (foreland and hinterland) basins should advance understanding of Andean topographic barriers, paleodrainage patterns, and their biological implications.