One of the fundamental questions in areas of large-magnitude extension and magmatism is the role of the mantle in the extension process. The Lake Mead area is ideally suited for developing models that link crustal and mantle processes because it contains both mantle and crustal boundaries and it was the site of large-magnitude crustal extension and magmatism during Miocene time. In the Lake Mead area, the boundary between the amagmatic zone and the northern Colorado River extensional corridor parallels the Lake Mead fault system and is situated just to the north of Lake Mead. This boundary formed between 11 and 6 Ma during, and just following, the peak of extension and corresponds to a contact between two mantle domains. During thinning and replacement of the lithospheric mantle in the northern Colorado River extensional corridor, the lithospheric mantle in the amagmatic zone remained intact. Contrasting behavior to the north and south of this boundary may have produced the mantle domain boundary. The domain to the north of the boundary is characterized by mafic lavas with a lithospheric mantle isotopic and geochemical signature (ϵNd = -3 to -9; 87Sr/86Sr = 0.706-0.707). To the south of the boundary in the northern Colorado River extensional corridor, lavas have an ocean island basalt (OIB)-mantle signature and appear to have only a minor lithospheric mantle component in their source (ϵNd = 0 to +4; 87Sr/86Sr = 0.703-0.705). Mafic lavas of the northern Colorado River extensional corridor represent the melting of a complex and variable mixture of asthenospheric mantle, lithospheric mantle, and crust. Pliocene alkali basalt magmas of the Fortification Hill field represent the melting of a source composed of a mixture of asthenospheric mantle, high U/Pb (HIMU)-like mantle, and lithospheric mantle. Depth of melting of alkali basalt magmas remained relatively constant from 12 to 6 Ma during, and just after, the peak of extension but probably increased between 6 and 4.3 Ma following extension. Miocene and Pliocene low ϵNd and high 87Sr/86Sr magmas and tholeiites at Malpais Flattop were derived from a lithospheric mantle source and were contaminated as they passed through the crust. The shift in isotopic values due to crustal interaction is no more than 4 units in ϵNd and 0.002 in 87Sr/86Sr and does not mask the character of the mantle source. The change in source of basalts from lithospheric mantle to asthenospheric mantle with time, the OIB character of the mafic lavas, and the HIMU-like mantle component in the source are compatible with the presence of rising asthenosphere, as an upwelling convective cell, or plume beneath the northern Colorado River extensional corridor during extension. The Lake Mead fault system, a major crustal shear zone, parallels the mantle domain boundary. The Lake Mead fault system may locally represent the crustal manifestation of differential thinning of the lithospheric mantle.