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The host dependence of mistletoes suggests that they track the distributions of their hosts. However, the factors that determine the geographic distribution of mistletoes are not well understood. In this study, the phylogeography of Psittacanthus sonorae was reconstructed by sequencing one nuclear (ITS) and two plastid (trnL-F and atpB-rbcL) regions of 148 plants from populations separated by the Sea of Cortez. Divergence time and gene flow were estimated to gain insight into the historical demography and geographic structuring of genetic variation. We also described and mapped the spatial distribution of suitable habitat occupied by P. sonorae and its most common host Bursera microphylla in the Sonoran Desert, along with their responses to Quaternary climate fluctuations using environmental data and ecological niche modeling (ENM). We detected environmental and genetic differentiation between the peninsular and continental P. sonorae populations. Population divergence occurred during the Pleistocene, around the time of the Last Glacial Maximum. No signals of population growth were detected, with net gene flow moving from the continent to the peninsula. ENM models indicate decoupled responses by the mistletoe and its main host to past climate changes. For the Last Interglacial to the present, most models produce only partial areas of overlap on both the peninsula and the continent. Our results support a scenario of Late-Pleistocene isolation and divergence with asymmetrical gene flow between peninsular and continental P. sonorae populations. Continental populations migrated to the peninsula and the spatial isolation probably produced genetic differentiation under different environmental conditions.