Cryptococcus neoformans is a major cause of fungal meningoencephalitis in immunocompromised patients. Despite recent advances in the genetics and molecular biology of C. neoformans, and improved techniques for molecular epidemiology, aspects of the ecology, population structure, and mode of reproduction of this environmental pathogen remain to be established. Application of recent insights into the life cycle of C. neoformans and its different ways of engaging in sexual reproduction under laboratory conditions has just begun to affect research on the ecology and epidemiology of this human pathogenic fungus. The melding of these disparate disciplines should yield rich dividends in our understanding of the evolution of microbial pathogens, providing insights relevant to diagnosis, treatment, and prevention.