This paper is a synthesis of Mississippian sedimentation on the southeastern, Appalachian margin of Laurussia. The Mississippian stratigraphic framework in the Appalachian area shows a large-scale, three-part, wedge-like, clastic‑carbonate-clastic sequence, which has been interpreted to be a likely flexural response to coeval Neoacadian Orogeny. Using an already established flexural framework and biostratigraphy, we have interpreted the approximate timing of flexural events based on biostratigraphy. These flexural events begin with active deformational loading that initiated rapid subsidence in the Appalachian foreland basin, during which the deeper-water, black Sunbury Shale and equivalents were deposited throughout the basin. Subsequent relaxational loading contributed to basin infilling through the deposition of a deeper-water, clastic succession, manifest as the extensive Cuyahoga-Logan-Borden-Grainger-Price-Rockwell-Pocono deltaic clastic wedge. By the time this clastic wedge had filled the foreland basin, clastic source areas in the orogen had apparently been lowered to the point that shallow seas migrated far eastward across former source areas. This brief period of equilibrium between the basin and source areas resulted in reduced clastic influx at a time when the basin entered subtropical latitudes, setting the stage for widespread carbonate deposition, represented by units like the Newman, Greenbrier, and Slade Limestones. Ensuing, rebound-related uplift, perhaps abetted by incipient, subsurface, Alleghanian thrusting, generated new sediment source areas and accompanying wedges of prograding marginal-marine and terrestrial sediment represented by the Pennington, Mauch Chunk and equivalent units. Marginal-marine sedimentation continued into Early Pennsylvanian time, when a combination of Alleghanian uplift and LPIA lowstand conditions generated a period of widespread, deep erosion that in many places across the Appalachian Basin destroyed substantial parts of the underlying Mississippian succession along the sub-Absaroka or “Mississippian-Pennsylvanian” unconformity. Although the basic Mississippian stratigraphic framework described above for the Appalachian Basin largely appears to be a consequence of Neoacadian flexural responses, major details regarding processes, timing and lithology were apparently controlled by concomitant interactions involving paleoclimate, eustasy, coeval Ouachita tectonism, and possibly early Alleghanian tectonism.