The putative Pliocene–Quaternary removal of mantle lithosphere from beneath the southern Sierra Nevada region (California, USA) is investigated by the iteration of thermal-mechanical models that incorporate and are tested against a range of data that are geologically observable, including rock uplift and basin subsidence data, structural and compositional data on crustal architecture, and a synthesis of seismic data that image lower crust–upper mantle structure of the region. The primary focus is testing model results with rock uplift and basin subsidence data. The initial state of our models recognizes that (1) the sub–Sierra Nevada batholith mantle lithosphere, including a substantial thickness of eclogitic cumulates that were produced during high magma flux arc activity, termed arclogite, was cooled to a conductive geotherm by amagmatic flat slab subduction at the end of the Cretaceous; and (2) the gravitationally metastable mantle lithosphere was thermally mobilized from beneath in the Neogene by the opening of an underlying slab window. Based on a detailed synthesis of appropriate rheologies of the multiphase system, a preferred class of models correctly predicts (1) the ca. 10 Ma inception of the Sierra Nevada microplate due to a lithospheric separation event along the eastern Sierra Nevada region as a result of the mobilization of the mantle lithosphere as a Rayleigh-Taylor instability; and (2) the subsequent delamination of the arclogite root of the Sierra Nevada batholith that appears to be in progress. Our preferred model also predicts focused rock uplift and basin subsidence resulting from delamination, both of which are anomalous to uplift and subsidence patterns of all other regions of the microplate. The rheology of the Great Valley crust is found to control rock uplift patterns across the Sierra Nevada, and tectonic subsidence in the Tulare Basin of the Great Valley. The Tulare Basin is uniquely situated over the region where the principal residual arclogite root remains attached to batholithic crust. The anomalous rock uplift and tectonic subsidence data are best satisfied by modeling a bulk rheology for the Great Valley crust that is similar to that of the Sierra Nevada batholith. These results are consistent with a recent synthesis of basement core and geophysical data showing that much of the Great Valley basement consists of the western Early Cretaceous zones of the Sierra Nevada batholith. The existence of this batholithic domain within the Great Valley subsurface is also in agreement with recent seismic data that resolve additional residual arclogite root materials along the base of the crust of this region.