The Amazonian Craton is an old geological feature of Archaean/Proterozoic age that has determined the character of fluvial systems in Amazonia throughout most of its past. This situation radically changed during the Cenozoic, when uplift of the Andes reshaped the relief and drainage patterns of northern South America. Here we review the sedimentary characteristics of Amazonian rivers and compare these with four fluvial depositional settings from the Meso-Cenozoic sedimentary record. These sedimentary units are the Alter do Chão Formation (Brazil, Late Cretaceous-Paleogene), the Petaca Formation (Bolivia, Late Oligocene to Middle Miocene), the Mariñame and Apaporis Sand Units (Colombia, Miocene), and the Iquitos White Sand Unit (Peru, Late Miocene-Pliocene). This review illustrates that the river systems born on the craton share features such as sediment texture and composition, depositional environments and transport directions. Evidence for the diminished role of cratonic fluvial systems and the onset of Neogene Andean uplift can be identified in the sedimentary record by changes in sediment provenance and transport directions. Although the Andean uplift and related processes discontinued the major Amazonian-born fluvial systems it also created new topographic features such as the Iquitos and Fitzcarrald Arches. These newly formed reliefs triggered a new generation of rivers, some of which are presently known as biodiversity hotspots.