The alternating mountain ranges and desert basins of the Great Basin in the western United States support higher species diversity of mammals than any other region of comparable area in temperate North America. Topographically complex regions have strong environmental gradients and heterogeneous habitats that result in fragmented geographic ranges over long periods and may promote speciation. In order to evaluate the influence of topography and climate on mammal diversification, we traced the history of mammal diversity during the formation of basin-and-range topography. We compiled species-occurrence data from the NeoMap database of fossil mammals and calculated standing diversity, origination rate, extinction rate, diversification rate (originations − extinctions), and turnover rate (originations extinctions) for million-year intervals. We evaluated changes in faunal composition (species in mammalian orders and species in rodent families) over time and assessed whether significant changes in diversity and faunal composition tracked major changes in landscape history. Neogene geologic evolution generated by tectonic activity and changing climate created the topographic complexity and habitat heterogeneity of the Great Basin. Over the last 30 million years, extensional tectonic processes caused an older high plateau to collapse and stretch from east to west, resulting in longitudinal expansion by ~235 km to form the Great Basin. Average elevation decreased by 1–3 km. Global warming and associated increases in regional precipitation from 17 to 14 million years ago (mya; the Miocene Climatic Optimum [MCO]) interrupted the long-term trend of Cenozoic cooling and aridification. From 30 to 2 mya, Great Basin mammal diversity peaked during the MCO, then declined over the later Miocene and Pliocene. The major changes in diversity over time were robust to sampling effects. Faunal composition changed episodically, with increasing proportions of rodents, lagomorphs, and carnivores and decreasing proportions of ungulates and proboscideans. The highest diversification rate occurred during the MCO with smaller but significant diversification rates later in the Neogene. The highest turnover rates occurred during and immediately following the MCO. Comparison of rodent faunas of the Great Basin and the Great Plains showed substantial differences in the timing and magnitude of diversification and changes in taxonomic composition. These patterns support the hypothesis that climate change over complex topography stimulated diversification in the Great Basin.