Evidence of former deep burial of Ordovician to Devonian strata of the northern Appalachian Basin has been obtained from various techniques of study, including fluid-inclusion homogenization temperatures, δ18O, and vitrinite reflectance. Diagenetic minerals indicate paleotemperatures of 100–200 °C. Maximum depths of burial were calculated from the estimated paleotemperatures; a gradient of 26 °C/km was assumed. Silurian strata of the basin are interpreted to have reached maximum burial depths of 5.0 km; Devonian strata in the Catskill Mountains had former burial depths of ∼6.5 km; Lower Ordovician carbonate sequences were buried to >7 km; Middle Ordovician strata had paleodepths of ∼5 km; and Devonian carbonate strata had paleodepths from 4.5 to 5 km. If these strata were buried deeper than previously thought, unexpectedly large amounts of uplift and erosion, ranging from 4.3 to 7 km, must also have taken place to bring these strata to the present land surface. The occurrence of such large-scale vertical movements of the crust and lithosphere must be recognized in paleogeographic reconstructions. Such drastic changes represent isostatic unroofing, with widespread implications for paleogeography of a kind unrecognized at present.