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The North American creosote bush (Larrea tridentata, Zygophyllaceae) is a widespread and ecologically dominant taxon of North American warm deserts. The species is comprised of diploid, tetraploid, and hexaploid populations, and touted as a classical example of an autopolyploid taxonomic complex. Here we use flow cytometry and DNA sequence data (non-coding cpDNA and nuclear ribosomal DNA) to evaluate spatial and evolutionary relationships among cytotype races, as well as the origins of the species from its South American ancestors. We find the geographic distribution of North American cytotypes to be highly structured, with limited co-occurrence within populations. Diploids reside only in the Chihuahuan Desert, as reported in previous biosystematic surveys, but tetraploid and hexaploid populations interdigitate along the margins of the Sonoran and Mojave Deserts. In phylogenetic analyses, North American plants comprise a monophyletic grouping that is sister to the South American diploid species, L. divaricata. North American populations exhibit genetic signatures of rapid demographic expansion, including a star-shaped genealogy, unimodal distribution of pairwise haplotype differences, and low genetic structure. Nonetheless, polyploid cytotypes are consistently distinguished from diploid cytotypes by a cpDNA indel character, suggesting a single origin of tetraploidy in the species. These findings suggest a recent origin of the North American creosote bush via long distance dispersal, with establishment of polyploid populations accompanying its rapid spread through the Northern Hemisphere.