Histoplasma capsulatum is well adapted to be infectious and pathogenic for humans. As a soil fungus with no known requirement for interacting with a mammalian host as part of an obligate lifecycle, its plethora of strategies for successful pathogenesis is particularly remarkable. These features include the dimorphic mold-yeast transition, entry into host macrophages, subcellular localization, intracellular survival and proliferation during active infection, and persistence during clinically inapparent infection with the capacity for reactivation. To thrive within the harsh environment of a professionally phagocytic and antimicrobial host cell, H. capsulatum displays mechanisms for modulating its microenvironmental pH level, resisting host reactive oxygen and nitrogen intermediates and degradative enzymes, and withstanding nutrient starvation conditions, including acquisition of iron and calcium and biosynthesis of nucleic acid precursors. Attention has been focused on identifying virulence-associated phenotypic traits and genes that are differentially expressed under relevant conditions, such as yeast morphotype-specific genes and genes that are up-regulated during infection. These studies, together with the increasing ability to perform molecular genetic manipulations in this fungus, may yield novel antifungal drug or vaccine targets as well as elucidating pathogenic mechanisms.