The Tsangpo Gorge region of the eastern Himalaya-Tibet is an exceptionally dynamic landscape, where the Yarlung-Siang-Brahmaputra River cuts through the high Himalaya in a zone of extremely localized rapid erosion and rock uplift. It has been argued that this area represents some of the best evidence for a localized positive feedback between erosion and deformation on Earth. We investigate this hypothesis by using detrital geochronology and thermochronology of modern river sediments and Cenozoic foreland basin deposits to establish the relative timing of river capture and the onset of rapid erosion/exhumation. Results rule out Pliocene river capture or Quaternary climate change as triggers for rapid exhumation, and instead point to a tectonic driver for extreme rock uplift rates. Quaternary megafloods (≥106 m3/s) sourced from valley blocking glaciers may have played an important role in eroding rapidly uplifted rock, and in the geomorphic evolution of the Gorge and Tibetan plateau margin. We investigate the sedimentary record and hydraulics of outburst floods through the Gorge, with implications for erosion and deposition in the largest source-to-sink sedimentary system on Earth. In the high-elevation source region, hydraulic flood simulations, field observations, and flood sediment provenance studies suggest (1) great potential for megaflood erosion in the Gorge, and (2) a lasting impact of megaflood deposits on the morphology and both river and hillslope processes in mountain landscapes. Previous studies show that megafloods have significantly altered landscapes in the sedimentary transfer zone between the headwaters and deepwater Bengal Fan and deposited material >2000 km offshore. Our ongoing work seeks to integrate geologic and human perspectives on flooding, landscape change, and sedimentation throughout this system, including Indigenous knowledge. Taken together, our findings show the profound legacy of episodic, large magnitude floods on mountain valley processes and on the transmission and preservation of tectonic and climatic signals in the sedimentary record.