Histoplasmosis results from infection with the fungal organism Histoplasma capsulatum. Most Histoplasma research today uses models based on primary pulmonary infection. Following inhalation, conidia are rapidly ingested and intracellularly convert to the yeast form. After initial pulmonary infection, organisms are carried throughout the body giving rise to disseminated infection. Three murine infection models have been developed which mimic human disease. These comprise models of primary infection following initial exposure to the organism, secondary exposure to Histoplasma following spontaneous recovery from primary disease and a model of reactivated infection following spontaneous clearance of primary disease. This chapter describes these models and explores variability introduced with the use of mice of varied genetic backgrounds and different H. capsulatum strains.