We quantitatively analyse the spatial pattern of deformation partitioning and of temporal accumulation of deformation in the Central Andes (15–26° S) with the aim of identifying those mechanisms responsible for initiating and controlling Cenozoic plateau evolution in this region. Our results show that the differential velocity between upper plate velocity and oceanic plate slab rollback velocity is crucial for determining the amount and rate of shortening, as well as their lateral variability at the leading edge of the upper plate. This primary control is modulated by factors affecting the strength balance between the upper plate lithosphere and the Nazca/South American Plate interface. These factors particularly include a stage of reduced slab dip (33 to 20 Ma) that accelerated shortening and an earlier phase (45 to 33 Ma) of higher trenchward sediment flux that reduced coupling at the plate interface, resulting in slowed shortening and enhanced slab rollback. Because high sediment flux and transfer of convergence into upper plate shortening constitute a negative feedback, we suggest that interruption of this feedback is critical for sustaining high shortening transfer, as observed for the Andes. Although we show that climate trends have no influence on the evolution of the Central Andes, the position of this region in the global arid belt in a low erosion regime is the key that provides this interruption; it inhibits high sediment flux into the trench despite the formation of relief from ongoing shortening. Along-strike variations in Andean shortening are clearly related to changes of the above factors. The spatial pattern of distribution of deformation in the Central Andes, as well as the synchronization of fault systems and the total magnitude of shortening, was mainly controlled by large-scale, inherited upper plate features that constitute zones of weakness in the upper plate leading edge. In summary, only a very particular combination of parameters appears to be able to trigger plateau-style deformation at a convergent continental margin. The combination of these parameters (in particular, differential trench-upper plate velocity evolution, high plate interface coupling from low trench infill, and the lateral distribution of weak zones in the upper plate leading edge) was highly uncommon during the Phanerozoic. This led to very few plateau-style orogens at convergent margins like the Cenozoic Central Andes in South America or, possibly, the Laramide North American Cordillera.