We investigate the NW-SE basement trends of the U.S. Midcontinent, often cited as Proterozoic in age. From a reduced-to-pole magnetic anomaly map, we map basement lineaments over an area of ~1.48 million km2. We compile published Ediacaran-Ordovician radiometric dates of intrusive rocks that suggest a deep crustal/mantle magma source for this time. Dolomite from one core provides one higher precision U-Pb date of 462 {plus minus}15 Ma and several lower precision dates that overlap this age range. Fluid inclusion, carbon, oxygen, and strontium isotope data indicate hot fluids were injected from deep in the basement relatively early in the Paleozoic. Even though the area has been structurally overprinted by late Paleozoic and later deformation, compilation of regional stratigraphic and structural data points strongly to widespread deformation in the latest Proterozoic to early Paleozoic. Taken together, these data indicate that the NW-SE basement trends are long-lived leaky transform faults associated with Iapetan rifting during the Ediacaran-Ordovician. These transform faults are interpreted as transtensional in part and leaky with respect to both magmatic emplacement and hot fluids from deeper in the basement. Our findings suggest a new model for the tectonic evolution of the U.S. Midcontinent, based on changing stress fields as subduction progresses south into Iapetus. This has implications for the origin of zones of weakness that are reactivated later, the distribution of aulacogens versus transforms, and the tectonic underpinnings of ore minerals deposited concurrently with the active faulting as well as oil and mineral deposits formed during their later reactivation.