New observations are presented on the character of Late Proterozoic-Early Cambrian, rift-related faulting in southeast Missouri. The principal fault set, which influences southeast Missouri structures, is composed of northwest-striking transfer faults. Initial Late Cambrian reactivations extended the faults northwest across the mid-continent and formed several major lineaments. Transpressive wrench-fault reactivations of these faults during Late Pennsylvanian-Early Permian time uplifted the St. Francois igneous terrane into a positive flower structure. This deformation was of an ancestral Rocky Mountain type (compressive block fault), and it produced the present structural framework of southeast Missouri. During Cretaceous rifting, the faults acted as transfer faults again, and intersections with related extension faults localized associated intrusive activity. These structures appear to be controlling present intraplate seismicity. These series of events indicate that the northwest striking transfer faults have been active for more than 600 m.y. Proper dentification of this faulting, its spacial relations, and its reactivations offer new understanding of present intraplate seismicity along the northwest margin of the Mississippi Embayment.