A pronounced, subparallel set of northeast-striking faults occurs in southeastern Missouri, but little is known about these faults because of poor exposure. The Commerce fault system is the southernmost exposed fault system in this set and has an ancestry related to Reelfoot rift extension. Recent published work indicates that this fault system has a long history of reactivation. The northeast-striking Grays Point fault zone is a segment of the Commerce fault system and is well exposed along the southeast rim of an inactive quarry. Our mapping shows that the Grays Point fault zone also has a complex history of polyphase reactivation, involving three periods of Paleozoic reactivation that occurred in Late Ordovician, Devonian, and post-Mississippian. Each period is characterized by divergent, right-lateral oblique-slip faulting. Petrographic examination of sidwall rip-out clasts in calcite-filled faults associated with the Grays Point fault zone supports a minimum of three periods of right-lateral oblique-slip. The reported observations imply that a genetic link exists between intracratonic fault reactivation and strain produced by Paleozoic orogenies affecting the eastern margin of Laurentia (North America). Interpretation of this link indicate that right-lateral oblique-slip has occurred on all of the northeast-striking faults in southeastern Missouri as a result of strain influenced by the convergence directions of the different Paleozoic orogenies.