Histoplasmosis is the most common endemic mycosis in the United States and has recently emerged as an important opportunistic infection among human immunodeficiency virus (HIV)-infected persons living in areas where it is endemic. In this article, we describe the epidemiologic and ecologic features of histoplasmosis, highlighting the implications for prevention. Surveillance and education of the public and health care providers are needed to determine the disease burden of histoplasmosis. Development of better diagnostic tests for detection of disease in humans and of the organism in the environment will help in designing better prevention strategies.