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Latest Pliocene to Quaternary, mildly alkaline, mafic to intermediate volcanic activity extends in a swath from the Lake Tahoe region in the eastern Sierra Nevada across the western Great Basin to the Battle Mountain area, Nevada. From west to east, the volcanic centers exhibit a dramatic gradient in chemical and isotopic composition. Centers situated in or adjacent to the Sierra Nevada have incompatible element and isotopic compositions consistent with an old, subduction-modified lithospheric mantle source (Sr-87/Sr-86 > 0.7045; Nd-143/Nd-144 < 0.5127; delta O-18 > +6.5 parts per thousand). Mafic volcanic centers east of the Sierra Nevada, in the Carson Sink and in the Buffalo Valley region, have an intraplate incompatible element and isotopic signature (Sr-87/Sr-86 < 0.7045; 143Nd/144Nd > 0.5127; delta O-18 < +6.5 parts per thousand) consistent with an asthenospheric mantle source. Earlier 20-3 Ma arc volcanism in the Sierra Nevada also tapped the old lithospheric mantle source along with the mantle wedge, indicating that the lithospheric mantle source existed well prior to the onset of Tertiary arc volcanism and probably prior to Mesozoic igneous activity of the Sierra Nevada. Thus, the lithospheric mantle beneath the Sierra Nevada has remained a geochemically consistent, fertile, fusible source for at least the past 20 m.y. Old lithospheric mantle likely still exists east of the Sierra Nevada, but lithospheric thinning and/or exhaustion of fusible components inhibit its melting, such that during the Quaternary, melting could only occur in the asthenosphere.