We make use of observations on orogenic strain accumulation and deformation partitioning in the Central Andes to explore the backarc strength evolution at the lithospheric scale. In plan view, the Altiplano-Puna plateaux experienced rapid initial increase of surface area undergoing active deformation during the Cenozoic. Beyond the maximum lateral extent reached around 10–15 Ma (40–50% of entire proto-Andes undergoing deformation) at 10–20% total strain, rapid localization initiated at the eastern flank of the Altiplano (Inter- and Subandean thrust belt) but not at the Puna latitude. Localization was associated with a significant increase in bulk shortening rate. Average fault slip rates equally increased by an order of magnitude following a protracted period of stable average rates. Estimates of strength evolution based on force balance calculations and critical wedge analysis suggest significant backarc weakening driving this change after the Middle Miocene. Strain accumulation led to localization and weakening with development of a detachment propagating through crust and upper mantle. We find that lithosphere-scale failure resulting from strain weakening beyond a critical strain threshold (c. 20%) and fault coalescence with formation of a weak detachment in shales (effective coefficient of friction < 0.1) plays a key role in the evolution of the Andes. Strain-related lithosphere weakening appears to dominate over the impact of external forcing mechanisms, such as variations of plate convergence, mantle-assisted processes, or erosion. Comparison of these orogen-scale observations with experimental rock rheology indicates substantial similarity of deformation behavior with similar weakening thresholds across a wide range of scales.