Epidemiologic reports routinely indicate that the high rate of HIV-1 transmission via mucosal exposure has been relatively stable since the epidemic began. Unfortunately, research on mucosal immune responses to HIV-1 has not been done in proportion to its importance. Most knowledge about immune responses against HIV-1 in humans comes from studies limited to the use of peripheral blood cells and plasma. Consequently, T-cell-based HIV-1 vaccines have long been considered a primary end point of preventive therapeutic strategies. The interest in HIV-1 exposed uninfected individuals has intensified because of the lessons to be learned about a natural immunologic response that promotes opposition to the infection. Such information has useful applications in the clinical setting. This review describes the current status of research on mucosal immune responses to HIV-1 from examining mucosal fluids and tissues of sexually exposed uninfected adults.