The Cenozoic geological evolution of the Central Andes, along two transects between ∼17.5°S and 21°S, is compared with paleo-topography, determined from published paleo-altimetry studies. Surface and rock uplift are quantified using simple 2-D models of crustal shortening and thickening, together with estimates of sedimentation, erosion, and magmatic addition. Prior to ∼25 Ma, during a phase of amagmatic flat-slab subduction, thick-skinned crustal shortening and thickening (nominal age of initiation ∼40 Ma) was focused in the Eastern and Western Cordilleras, separated by a broad basin up to 300 km wide and close to sea level, which today comprises the high Altiplano. Surface topography at this time in the Altiplano and the western margin of the Eastern Cordillera appears to be ∼1 km lower than anticipated from crustal thickening, which may be due to the pull-down effect of the subducted slab, coupled to the overlying lithosphere by a cold mantle wedge. Oligocene steepening of the subducted slab is indicated by the initiation of the volcanic arc at ∼27–25 Ma, and widespread mafic volcanism in the Altiplano between 25 and 20 Ma. This may have resulted in detachment of mantle lithosphere and possibly dense lower crust, triggering 1–1.5 km of rapid uplift (over ≪5 Myrs) of the Altiplano and western margin of the Eastern Cordillera and establishing the present day lithospheric structure beneath the high Andes. Since ∼25 Ma, surface uplift has been the direct result of crustal shortening and thickening, locally modified by the effects of erosion, sedimentation, and magmatic addition from the mantle. The rate of crustal shortening and thickening varies with location and time, with two episodes of rapid shortening in the Altiplano, lasting <5 Myrs, that are superimposed on a long-term history of ductile shortening in the lower crust, driven by underthrusting of the Brazilian Shield on the eastern margin.