Miocene volcanic rocks in the Pinacate area, Sonora, record a progressive change in the source of magmatism induced by asthenospheric upwelling and lithospheric thinning. 40Ar/39Ar age data, mineral chemistry, and major- and trace-element contents allow the identification of two volcanic sequences: an oldest basaltic episode (ca. 20 Ma), and a middle Miocene (12–15.5 Ma) sequence that consists of mesa basalts with transitional alkali character, calc-alkaline dacites, and high-silica rhyolites evolving toward peral-kaline liquids. Sr, Nd, and Pb isotope ratios reveal different sources for the Miocene basalts. The easternmost basalts have signatures indicating a Precambrian lithospheric mantle source, while the westernmost tholeiitic to transitional basalts are related to mixing of lithospheric and asthenospheric mantle. Rhyolites are the result of fractional crystallization of transitional basalt magmas with slight contamination by Precambrian crust. Chemical modeling shows that peralkaline rhyolites are related to slightly higher assimilation during their residence in the upper crust but also to a change in the mantle source of the parent basalt. The evolution of the isotopic signatures in space and time indicates that: (1) the volcanic activity is located over a major lithospheric boundary, i.e., the western limit of the North American Craton; (2) the lithosphere was progressively thinned so that huge volumes of alkalic basalts could access the surface during the Quaternary, building the Pinacate Volcanic Field. Correlation between geochemical signatures and the tectonic evolution of the western margin of the North American Craton shows that a progressive change in the source of magmatism can be related to the development of a slab window during the Miocene.