We investigated the evolutionary history of a group of silky pocket mice (Heteromyidae: Perognathinae: Perognathus flavus species group) composed of the species P. flavus and P. merriami to determine patterns and postulate causes of geographical diversification across arid grasslands and intermontane basins in western North America. The region represents a topographically complex landscape with a Neogene history of dramatic geological and climatic transformations. Phylogenetic and dating analyses of mitochondrial DNA support an initial split among 4 major lineages during the late Miocene, and this hypothesis receives further support from analysis of a portion of the nuclear interphotoreceptor retinoid-binding protein (IRBP) gene. Two of these lineages have a restricted geographic distribution in the Chihuahuan Desert, and 2 have distributions ranging across large portions of the Chihuahuan Desert, Colorado Plateau, Great Plains, and Tamaulipan Plain. Within the 2 widespread lineages further geographical diversification likely was concentrated in the Pliocene, which coincided with the origin of several hypothesized geographic barriers. These results are consistent with models of allopatric divergence driven by pre-Pleistocene geological and climatic events, particularly the late-Miocene expansion of interior grasslands and Miocene–Pliocene evolution of Basin and Range geomorphology. Therefore, the biogeographic structure displayed in the flavus species group may be predictive for a range of sympatric taxa.