Deformation in the orogen-foreland system of the southern Central Andes between 33° and 36° S varies in style, locus, and amount of shortening. The controls that determine these spatially variable characteristics have largely remained unknown, yet both the subduction of the oceanic Nazca plate and the strength of the South American plate have been invoked to play a major role. While the parameters governing the subduction processes are similar between 33° and 36° S, the lithospheric strength of the upper plate is spatially variable due to structures inherited from past geodynamic regimes and associated compositional differences in the South American plate. Regional Mesozoic crustal horizontal extension generated a < 40-km-thick crust with a more mafic composition in the lower crust south of 35°S; north of this latitude, however, a more felsic lower crust is inferred from geophysical data. To assess the influence of different structural and compositional heterogeneities on the style of deformation in the southern Central Andes, we developed a suite of geodynamic models of intraplate lithospheric shortening for two E–W transects (33° 40′ S and 36° S) across the Andes. The models are constrained by local geological and geophysical information. Our results demonstrate a decoupled shortening mode between the brittle upper crust and the ductile lower crust in those areas characterized by a mafic lower crust (36° S transect). In contrast, a more felsic lower crust, such as in the 33° 40′ S transect, results in a coupled shortening mode. Furthermore, we find that differences in lithospheric thickness and the asymmetry of the lithosphere–asthenosphere boundary may promote the formation of a crustal-scale, west-dipping detachment zone that drives the overall deformation and lateral expansion of the orogen. Our study represents the first geodynamic modeling effort in the southern Central Andes aimed at understanding the roles of heterogeneities (crustal composition and thickness) at the scale of the entire lithosphere as well as the geometry of the lithosphere–asthenosphere boundary with respect to mountain building. Fil: Barrionuevo, Matías. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Liu, Sibiao. Universitat Potsdam; Alemania Fil: Mescua, Jose Francisco. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Yagupsky, Daniel Leonardo. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Ciudad Universitaria. Instituto de Estudios Andinos "Don Pablo Groeber". Universidad de Buenos Aires. Facultad de Ciencias Exactas y Naturales. Instituto de Estudios Andinos "Don Pablo Groeber"; Argentina Fil: Quinteros, Javier. German Research Centre for Geosciences; Alemania Fil: Giambiagi, Laura Beatriz. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Provincia de Mendoza. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales. Universidad Nacional de Cuyo. Instituto Argentino de Nivología, Glaciología y Ciencias Ambientales; Argentina Fil: Sobolev, Stephan V.. Universitat Potsdam; Alemania Fil: Piceda, Constanza Rodríguez. Universitat Potsdam; Alemania Fil: Strecker, Manfred R.. German Research Centre for Geosciences; Alemania