The Rhine Rift System (RRS) forms part of the European Cenozoic Rift System (ECRIS) and transects the Variscan Orogen, Permo-Carboniferous troughs and Late Permian to Mesozoic thermal sag basins. Crustal and lithospheric thicknesses range in the RRS area between 24-36 km and 50-120 km, respectively. We discuss processes controlling the transformation of the orogenically destabilised Variscan lithosphere into an end-Mesozoic stabilised cratonic lithosphere, as well as its renewed destabilisation during the Cenozoic development of ECRIS. By end-Westphalian times, the major sutures of the Variscan Orogen were associated with 45-60 km deep crustal roots. During the Stephanian-Early Permian, regional exhumation of the Variscides was controlled by their wrench deformation, detachment of subducted lithospheric slabs, asthenospheric upwelling and thermal thinning of the mantlelithosphere. By late Early Permian times, when asthenospheric temperatures returned to ambient levels, lithospheric thicknesses ranged between 40 km and 80 km, whilst the thickness of the crust was reduced to 28-35 km in response to its regional erosional and local tectonic unroofing and the interaction of mantle-derived melts with its basal parts. Re-equilibration of the lithosphere-asthenosphere system governed the subsidence of Late Permian-Mesozoic thermal sag basins that covered much of the RRS area. By end-Cretaceous times, lithospheric thicknesses had increased to 100-120 km. Paleocene mantle plumes caused renewed thermal weakening of the lithosphere. Starting in the late Eocene, ECRIS evolved in the Pyrenean and Alpine foreland by passive rifting under a collision-related north-directed compressional stress field. Following endOligocene consolidation of the Pyrenees, west-and northwest-directed stresses originating in the Alps controlled further development of ECRIS. The RRS remained active until the Present, whilst the southern branch of ECRIS aborted in the early Miocene. Extensional strain across ECRIS amounts to some 7 km. Plume-related thermal thinning of the lithosphere underlies uplift of the Rhenish Massif and Massif Central. Lithospheric folding controlled uplift of the VosgesBlack Forest Arch.