Eucnide (Loasaceae) consists of about 15 species distributed across Mexico, Guatemala, and the North American Southwest, a geographically complex landscape made up of floristically unique deserts, large mountain ranges, and a large, geographically isolated peninsula. This complex geography is credited for high levels of biodiversity and endemism in the region and we examine relationships between geography and cladogenesis in Eucnide. In the most recent treatment of the genus, Thompson and Ernst recognize three sections of Eucnide differentiated based on floral morphology. To date, no molecular phylogenetic studies have broadly sampled species in this genus. We used Bayesian and maximum-likelihood phylogenetic analyses of one plastid marker (matK) and one nuclear marker (ITS) to: 1) test the monophyly of Eucnide sections and assess whether the existing taxonomy sufficiently circumscribes diversity within the genus; 2) assess the divergence times of Eucnide lineages to determine when the major clades diversified; and 3) estimate the ancestral range of Eucnide and hypothesize patterns of geographical diversification of the genus. We found that not all infrageneric units of Eucnide are monophyletic and the taxonomy needs revision. Additionally, the major clades of Eucnide are predominantly restricted to geographic regions, suggesting that species have frequently diversified within geographic areas. The ancestral range of Eucnide was inferred to be widespread, and the divergence times of the major clades coincide with major geological events, particularly, the formation of the North American warm deserts, the isolation of the Baja Peninsula, and the uplift of the Trans Mexican Volcanic Belt. This suggests that major geological/climatic events may have contributed to the diversification of the genus.