Over the past decade, opportunistic fungal infectious diseases have increased in prevalence as the population of immunocompromised individuals escalated due to HIV/AIDS and immunosuppression associated with organ transplantation and cancer therapies. In the three predominant human pathogenic fungi (Candida albicans, Cryptococcus neoformans, and Aspergillus fumigatus), a unifying feature is that all three retained the machinery needed for sex, and yet all limit their access to sexual reproduction. While less well characterized, many of the other human pathogenic fungi also appear to have the ability to undergo sexual reproduction. Recent studies with engineered pairs of diploid strains of the model yeast Saccharomyces cerevisiae, one that is sexual and the other an obligate asexual, provide direct experimental validation of the benefits of both sexual and asexual reproduction. The obligate asexual strain had an advantage in response to constant environmental conditions whereas the sexual strain had a competitive edge under stressful conditions (Goddard et al., 2005; Grimberg and Zeyl, 2005). The human pathogenic fungi have gone to great lengths to maintain all of the machinery required for sex, including the mating-type locus and the pheromone response and cell fusion pathways. Yet these pathogens limit their access to sexual or parasexual reproduction in unique and specialized ways. Our hypothesis is that this has enabled the pathogenic fungi to proliferate in their environmental niche, but to also undergo genetic exchange via sexual reproduction in response to stressful conditions such as new environments, different host organisms, or changes in the human host such as antimicrobial therapy. Further study of the sexual nature of the human pathogenic fungi will illuminate how these unique microbes have evolved into successful pathogens in humans.