Several generations of the ancestral Pee Dee River system have been mapped beneath the South Carolina Grand Strand coastline and adjacent Long Bay inner shelf. Deep boreholes onshore and high-resolution seismic-reflection data offshore allow for reconstruction of these paleochannels, which formed during glacial lowstands, when the Pee Dee River system incised subaerially exposed coastal-plain and continental-shelf strata. Paleochannel groups, representing different generations of the system, decrease in age to the southwest, where the modern Pee Dee River merges with several coastal-plain tributaries at Winyah Bay, the southern terminus of Long Bay. Positions of the successive generational groups record a regional, southwestward migration of the river system that may have initiated during the late Pliocene. The migration was primarily driven by barrier-island deposition, resulting from the interaction of fluvial and shoreline processes during eustatic highstands. Structurally driven, subsurface paleotopography associated with the Mid-Carolina Platform High has also indirectly assisted in forcing this migration. These results provide a better understanding of the evolution of the region and help explain the lack of mobile sediment on the Long Bay inner shelf. Migration of the river system caused a profound change in sediment supply during the late Pleistocene. The abundant fluvial source that once fed sand-rich barrier islands was cut off and replaced with a limited source, supplied by erosion and reworking of former coastal deposits exposed at the shore and on the inner shelf.