Western Tibet, between the Karakorum fault and the Gozha–Longmu Co fault system, is mostly internally drained and has a 1.5–2 km amplitude relief with km-large valleys. We investigate the origin of this peculiar morphology by combining a topography analysis and a study of the Cenozoic sedimentation in this area. Cenozoic continental strata correspond to a proximal, detrital fan deposition, and uncomformably rest on a palaeorelief similar to the modern one. Zircon U–Pb dating from trachytic flows interbedded within the Cenozoic continental sediments indicates that detrital sedimentation occurred at least between ca 24 and 20 Ma in the Shiquanhe basin, while K/Ar ages suggest it may have started since ~ 37 Ma in the Zapug basin. The distribution of continental deposits shows that present-day morphology features, including km-large, 1500 m-deep valleys, were already formed by Early Miocene times. We suggest that today's internally drained western Tibet was externally drained, at least during late Miocene, contemporaneously with early motion along the Karakorum Fault. Detailed study of the present day river network is compatible with a dextral offset on the Karakorum Fault of 250 km at a rate of ~ 10 ± 1 mm/yr. Displacement along the Karakorum fault possibly induced the shift from external to an internal drainage system, by damming of the Bangong Co ~ 4 Ma ago, leading to the isolation and preservation of the western Tibet relief.