Recent research in the Himalayan fold-thrust belt provides two new sets of observations that are crucial to understanding the evolution of the Himalayan-Tibetan orogenic system. First, U-Pb zircon ages and Sm-Nd isotopic studies demonstrate that (1) Greater Himalayan medium- to high-grade metasedimentary rocks are much younger than true Indian cratonic basement; and (2) these rocks were tectonically mobilized and consolidated with the northern margin of Gondwana during early Paleozoic orogenic activity. These observations require that Greater Himalayan rocks be treated as supracrustal material in restorations of the Himalayan fold-thrust belt, rather than as Indian cratonic basement. In turn, this implies the existence of Greater Himalayan lower crust that is not exposed anywhere in the fold-thrust belt. Second, a regional compilation of shortening estimates along the Himalayan arc from Pakistan to Sikkim reveals that (1) total minimum shortening in the fold-thrust belt is up to ∼670 km; (2) total shortening is greatest in western Nepal and northern India, near the apex of the Himalayan salient; and (3) the amount of Himalayan shortening is equal to the present width of the Tibetan Plateau measured in an arc-normal direction north of the Indus-Yalu suture zone. This information suggests that a slab of Greater Indian lower crust (composed of both Indian cratonic lower crust and Greater Himalayan lower crust) with a north-south length of ∼700 km may have been inserted beneath the Tibetan crust during the Cenozoic orogeny. We present a modified version of the crustal underthrusting model for Himalayan-Tibetan orogenesis that integrates surface geological data, recent results of mantle tomographic studies, and broadband seismic studies of the crust and upper mantle beneath the Tibetan Plateau. Previous studies have shown that incremental Mesozoic and early Cenozoic shortening had probably thickened Tibetan crust to ∼45–55 km before the onset of the main Cenozoic orogenic event. Thus, the insertion of a slab of Greater Indian lower crust with maximum thickness of ∼20 km (tapering northward) could explain the Cenozoic uplift of the Tibetan Plateau. The need for Tibetan crust to stretch laterally as the Greater Indian lower crust was inserted may explain the widespread east-west extension in the southern half of the Plateau. Our reconstruction of the Himalayan fold-thrust belt suggests that Indian cratonic lower crust, of presumed mafic composition and high strength, should extend approximately halfway across the Tibetan Plateau, to the Banggong suture. From there northward, we predict that the Tibetan Plateau is underlain by more felsic, and therefore weaker, lower crust of Greater Himalayan affinity. Two slab break-off events are predicted by the model: the first involved Neotethyan oceanic lithosphere that foundered ∼45–35 Ma, and the second consisted of Greater Indian lithosphere (most likely composed of Greater Himalayan material) that delaminated and foundered ∼20–10 Ma. Asthenospheric upwelling associated with the break-off events may explain patterns of Cenozoic volcanism on the Tibetan Plateau. Although the model predicts a northward migrating topographic front due solely to insertion of Greater Indian lower crust, the actual uplift history of the Plateau was complicated by early-middle Tertiary shortening of Tibetan crust.