Studies of field- and patient-derived isolates conducted over the past 75 years have provided a general picture of the population structure of Coccidioides, the cause of coccidioidomycosis. Premolecular studies provided a general outline of the geographical range, epidemiology and distribution of the fungus. Recent studies based on molecular markers have demonstrated that the genus is comprised of two genetically diverse, and genetically isolated, species: Coccidioides immitis and C. posadasii. Both species are composed of biogeographically distinct populations. Structure for two of these populations (C. immitis from central California, and C. posadasii from southern Arizona) indicates that frequent genetic recombination occurs within the entire geographic range of each population, even though sex has never been observed in the genus. Outbreaks of coccidioidomycosis are not the result of the spread of a single clonal isolate, but are caused by a diversity of genotypes. Although it is now possible to match patient isolates to populations, the lack of apparent structure within each population and the current paucity of environmental isolates limit map-based epidemiological approaches to understanding outbreaks. Therefore, a comprehensive database comprised of soil-derived isolates from across the biogeographic range of Coccidioides will improve the utility of this approach. Appropriate collection of environmental isolates will assist the investigation of remaining questions regarding the population biology of Coccidioides. The comparative genomics of representative genotypes from both species and all populations of Coccidioides will provide a thorough set of genetic markers in order to resolve the population genetics of this pathogenic fungus.