The eastern margin of North America has been shaped by a series of tectonic events including the Paleozoic Appalachian Orogeny and the breakup of Pangea during the Mesozoic. For the past ~200 Ma, eastern North America has been a passive continental margin; however, there is evidence in the Central Appalachian Mountains for post-rifting modification of lithospheric structure. This evidence includes two co-located pulses of magmatism that post-date the rifting event (at 152 Ma and 47 Ma) along with low seismic velocities, high seismic attenuation, and high electrical conductivity in the upper mantle. Here, we synthesize and evaluate constraints on the lithospheric evolution of the Central Appalachian Mountains. These include tomographic imaging of seismic velocities, seismic and electrical conductivity imaging along the MAGIC array, gravity and heat flow measurements, geochemical and petrological examination of Jurassic and Eocene magmatic rocks, and estimates of erosion rates from geomorphological data. We discuss and evaluate a set of possible mechanisms for lithospheric loss and intraplate volcanism beneath the region. Taken together, recent observations provide compelling evidence for lithospheric loss beneath the Central Appalachians; while they cannot uniquely identify the processes associated with this loss, they narrow the range of plausible models, with important implications for our understanding of intraplate volcanism and the evolution of continental lithosphere. Our preferred models invoke a combination of (perhaps episodic) lithospheric loss via Rayleigh-Taylor instabilities and subsequent small-scale mantle flow in combination with shear-driven upwelling that maintains the region of thin lithosphere and causes partial melting in the asthenosphere.