There are individuals who despite being exposed to HIV, in some cases repeatedly and over long periods, remain without HIV seroconversion. These individuals are called HIV-exposed seronegatives, and have been reported among commercial sex workers, men having sex with men, injection drug users, hemophiliacs who received contaminated blood preparations, healthcare workers with accidental percutaneous exposure to HIV-infected blood, infants born to HIV-infected mothers, and individuals having HIV-positive heterosexual partners. Genetic and immunological mechanisms have been involved in the production of this resistance to HIV acquisition. Genetic factors have been linked to genes encoding chemokine receptors and their natural ligands as well as genes of the major histocompatibility complex. Immunological factors are grouped within both innate and adaptive immunity. The study of HIV-exposed seronegatives provides a unique opportunity to understand the mechanisms of natural protection against HIV infection. The better understanding of this protection may lead to novel preventive and immunotherapeutic approaches, including vaccines.