Pre-existing weakness due to repeated tectonic, metamorphic, and magmatic events is a fundamental feature of the continental lithosphere on Earth. Because of this, continental deformation results from a combined effect of boundary conditions imposed by plate tectonic processes and heterogeneous and anisotropic mechanical strength inherited from protracted continental evolution. In this study, we assess how this interaction may have controlled the Cenozoic evolution of the eastern Tibetan plateau during the India–Asia collision. Specifically, we use analogue models to evaluate how the pre-Cenozoic structures may have controlled the location, orientation, and kinematics of the northwest-striking Xianshuihe and northeast-striking Longmen Shan fault zones, the two most dominant Cenozoic structures in eastern Tibet. Our best model indicates that the correct location, trend, and kinematics of the two fault systems can only be generated and maintained if the following conditions are met: (1) the northern part of the Songpan–Ganzi terrane in eastern Tibet has a strong basement whereas its southern part has a weak basement, (2) the northern strong basement consists of two pieces bounded by a crustal-scale weak zone that is expressed by the Triassic development of a northwest-trending antiform exposing middle and lower crustal rocks, and (3) the region was under persistent northeast–southwest compression since ∼35 Ma. Our model makes correct prediction on the sequence of deformation in eastern Tibet; the Longmen Shan right-slip transpressional zone was initiated first as an instantaneous response to the northeast–southwest compression, which is followed by the formation of the Xianshuihe fault about a half way after the exertion of northeast–southwest shortening in the model. The success of our model highlights the importance of pre-existing weakness, a key factor that has been largely neglected in the current geodynamic models of continental deformation.