Histoplasma capsulatum is a dimorphic ascomycete which is capable of producing a broad spectrum of disease ranging from mild asymptomatic, pulmonary illness to severe, life-threatening systemic mycosis. Regulatory mechanisms that use temperature and other environmental cues are paramount to the successful adaptation of the organism as an effective intracellular pathogenic yeast. Although the biochemistry and phenomenology of reversible morphogenesis have been well examined in Histoplasma, the identification and functional characterization of genes and their products that are required for early establishment or maintenance of the parasitic yeast phase in intracellular host compartments have only recently been fruitful. Advances in the molecular biology of Histoplasma, including approaches to introduce telomeric plasmids, reporter fusion constructs, and gene disruption cassettes into the fungus are poised to solidify the pre-eminence of this fungus as a model system which can be applied to other dimorphic fungal pathogens that exhibit similar cellular and immunological complexities. This review centers on recent developments in the molecular cell biology and molecular genetics of Histoplasma capsulatum that provide important new avenues for examining the mold-to-yeast phase transition beyond the historical, binary view of dimorphism and the implications that these successful approaches may have on seminal issues in fungal pathogenesis.