Geochronologic data from the southern margins of the Colorado Plateau (western United States) show an inboard radial migration of Neogene basaltic magmatism. Nd and Sr isotopic data show that as basaltic volcanism migrates inboard it also becomes increasingly more asthenospheric. Strongly asthenospheric alkali basalt (εNd > 4) appeared on the western plateau margin ca. 5 Ma, on the southeastern margin at 7 Ma, and is lacking from the plateau's other margins. Tomographic data suggest that low-velocity mantle underlies almost all recent (younger than 1 Ma) basaltic volcanism in a ring around much of the Colorado Plateau at a depth of 80 km. The combined isotopic and tomographic data indicate that the low-velocity mantle is asthenosphere along the western and southeastern margins of the plateau, but modified lithosphere around the remaining margins. Temporal and spatial patterns suggest a process by which upwelling asthenosphere is progressively infiltrating and replacing lithospheric mantle, especially where Proterozoic boundaries exist. This model explains (1) the dramatic velocity contrast seen well inboard of the physiographic edge of the plateau, (2) the inboard sweep of Neogene magmatism, and (3) isotopic evidence that much (but not all) of the low-velocity mantle is asthenospheric. These data support models that ongoing uplift of the edges of the Colorado Plateau is driven by mantle processes.