Tertiary volcanic rocks were erupted across the Mojave Desert and southeastern California in the early to middle Miocene after a long period of magmatic quiescence. Eruption of these rocks generally coincided with regional extension. New Sr, Nd, and whole-rock Pb isotopic data for Miocene rocks, from a transect from the western Mojave Desert to the Colorado River trough, provide clues to crustal and mantle structure during this important time period. Volcanism was calc-alkalic but transitional to alkalic in the eastern part of the area. Trace element contents, trace element ratios, and radiogenic isotopic compositions vary across the study area, and isotopic composition is correlated with both bulk chemical composition and longitude. Correlation of isotopic composition with bulk composition results from widespread contamination of mantle-derived basalts with crust. Variation of isotopic composition versus longitude for rocks of all bulk compositions reflects longitudinal variations in both mantle and crustal structure. Geochemical signatures of mafic rocks east of about long 116°W indicate an ancient (Precambrian) enriched lithosphere source. Some thinned and/or reworked Precambrian crust extends west of 116°W. Mafic rocks west of 116°W were derived from mantle with oceanic geochemical and isotopic signatures. There is no clear, coincident, major crustal structure or tectonic boundary in surface geology at 116°W; however, modern-day seismicity is restricted to areas west of this longitude, and there is a change in the dominant orientation of mountain ranges at this longitude. The data here also indicate that the long-standing problem of drawing the Sri = 0.706 line through the Mojave Desert can be resolved if the line represents the west edge of the North American mantle rather than Precambrian crust. By this definition, the Sri = 0.706 line would be the isotopic boundary at 116°W. The cause of early Miocene volcanism in the Mojave Desert remains enigmatic. An oceanic mantle source for early Miocene basalts in the western Mojave Desert suggests a possible connection to asthenospheric mantle volcanism in the California Coast Ranges. Simple models of decompression melting of enriched mantle following convective thinning and extension of the lithosphere cannot be applied across the Mojave Desert.