The tectonic evolution of the North American Gulf of Mexico continental margin is characterized by two Wilson cycles, i.e., repeated episodes of opening and closing of ocean basins along the same structural trend. This evolution includes (1) the Precambrian Grenville orogeny; (2) formation of a rift-transform margin during late Precambrian opening of the Iapetus Ocean; (3) the late Paleozoic Ouachita orogeny during assembly of Pangea; and (4) Mesozoic rifting during opening of the Gulf of Mexico. Unlike the Atlantic margins, where Wilson cycles were first recognized, breakup in the Gulf of Mexico did not initially focus within the orogen, but was instead accommodated within a diffuse region adjacent to the orogen. This variation in location of rifting is a consequence of variations in the prerift architecture of the orogens. The Appalachian-Caledonian orogeny involved substantial crustal shortening and formation of a thick crustal root. In contrast, the Ouachita orogeny resulted in minimal crustal shortening and thickening. In addition, rather than a crustal root, the Ouachita orogen was underlain by the lower plate of a relatively pristine Paleozoic subduction system that is characterized by a shallow mantle. A finite element model simulating extension on the margin demonstrates that this preexisting structure exerted fundamental controls on the style of Mesozoic rifting. The shallow mantle created a strong lithosphere beneath the orogen, causing extension to initiate adjacent to, rather than within, the orogen. On the Atlantic margins, the thick crustal root resulted in a weak lithosphere and initiation of extension within the interior of the orogen. Major features of the modern Gulf of Mexico margin, including the Interior Salt Basin, outboard unextended Wiggins arch, and an unusually broad region of extension beneath the coastal plain and continental shelf, are direct consequences of the prerift structure of the margin.