Along the Laramide belt of northwestern Mexico, granitic rocks of similar bulk composition show isotopic and trace element signatures that help to delineate the position of the southern edge of the North American Precambrian basement. In the northern part, the Laramide plutons (the “northern granites”) intruded Proterozoic crystalline rocks and a thick Late Proterozoic through Paleozoic miogeoclinal cover of North American affinity. In the central part, the granitic bodies (the “central granites”) were emplaced into a sequence of Paleozoic eugeoclinal rocks overlain by Late Triassic clastic units. The southern part of the belt (the “southern granites”) intruded a less-known crust characterized by middle to late Mesozoic island-arc–related volcanic and sedimentary rocks of the Guerrero terrane. Data from a suite of metaluminous to slightly peraluminous calc-alkalic granitic rocks along the belt display north-to-south geochemical and isotopic variations, which could correlate with the type of intruded basement. The northern and central granites are characterized by strongly fractionated, light rare earth element (REE)–enriched patterns, which display generally pronounced negative europium anomalies, whereas the southern granites have lower total REE enrichments and much flatter chondrite-normalized slopes displaying almost no europium anomalies. Isotopic results also suggest regional variations, as shown by the following initial Sr and ϵNd ranges: 0.7070 to 0.7089 and−4.2 to−5.4, respectively, for the northern granites; 0.7060 to 0.7079 and−3.4 to−5.1 for the central granites; and 0.7026 to 0.7062 and−0.9 to +4.2 for the southern granites. On the basis of their isotopic similarities, the Proterozoic mafic to intermediate lower crust revealed by xenoliths from young volcanic flows in southern Arizona and northern Mexico is interpreted as a reasonable parental source for the northern and central granites; however, mantle-derived melts are not excluded. The more primitive southern granites are interpreted to come from a source that lacked Proterozoic basement. Instead, they were probably derived by mixing of juvenile mantle melts with partial melts of the lower parts of the Guerrero terrane. In general, the north-to-south compositional variations of the Laramide granitic rocks of northwestern Mexico reflect the crustal structure underneath the batholiths. The Sr and Nd data indicate that the edge of the North American Precambrian basement extends approximately southeastward from the coastal batholith of central Sonora; then, about 200 km south of Hermosillo in southern Sonora, the edge bends eastward and continues to the east beneath the Sierra Madre Occidental volcanic province.