Late Cenozoic alkalic and tholeiitic basalts from the Rio Grande rift region display a wide range of Nd and Sr isotopic compositions which indicate the involvement of “enriched” mantle (EM), “depleted” mantle (DM), and crust in basalt petrogenesis. Isotopic compositions of alkali basalts (this study and published data) reflect the characteristics of their mantle source and correlate with tectonic setting: In the southern Basin and Range, a region of pronounced lithospheric extension and thinning, alkali basalts with εNd = +7 to +8 are derived from DM, which corresponds to upwelled, oceanic‐type asthenosphere; alkali basalts from the Great Plains, northern Rio Grande rift, and eastern Colorado Plateau, regions which have undergone less lithospheric extension, have distinctly different isotopic compositions (εNd = 0 to + 2) and were derived from EM; alkali basalts from the southeastern Colorado Plateau‐Basin and Range transition zone have isotopic compositions that are intermediate between DM and EM values (εNd = + 6.6 to + 3.3) and were derived from the DM/EM boundary. The correlation of isotopic signatures and upper mantle geophysical properties with tectonic setting suggests a physical model for the evolution of basalt sources during lithospheric extension and rifting. Prior to regional extension and rifting, EM corresponds to lithospheric mantle with a history of trace element enrichment and isolation from the underlying asthenosphere. Once rifting begins, lithospheric extension and asthenospheric up‐welling lead to thermal thinning and conversion of lithospheric mantle to asthenosphere. EM can take on asthenospheric physical properties, yet remain intact and a source of basalts until, at an advanced stage of rifting, it is physically replaced by convective mixing with the underlying DM/astheriosphere. Tholeiites, because they equilibrate at shallower depths than alkali basalts, generally equilibrate within EM. In contrast to alkali basalts, tholeiites typically are crustally contamined, probably because their lower volatile contents inhibit their ascent through the crust. Throughout much of the region, tholeiites assimilated small amounts ( < 10%) of middle to upper crustal wall rock. In contrast, a variety of volcanic rocks (including tholeiites) from within the rift have assimilated lower crustal wall rock, probably because the background temperatures in the lower crust of the rift are higher and because these rocks are associated with large‐volume, long‐lived volcanic fields that locally enhance thermal input into the lower crust. Lithospheric mantle of the Rio Grande rift region is younger than lithospheric mantle beneath the Archean craton to the north (1.7 versus 2.7 b.y. old), which is compatible with the higher εNd values of EM‐derived volcanic rocks of the rift region. A “plum pudding” model of the mantle, in which the least refractory, more incompatible‐element‐enriched heterogeneities preferentially determine the isotopic composition of melts, can account for the isotopic compositions of basalts in the rift region.