Since the beginning of the AIDS pandemic, and following the discovery of the human immunodeficiency virus (HIV) as the etiological agent of the disease, it was clear that the virus gains access to the human host predominantly through the mucosal tissue after sexual exposure. As a consequence, the female genital tract (vaginal and cervical), as well as the rectal, penile, and oral mucosae have been extensively studied over the last thirty years towards a better understanding of--and to develop strategies to prevent--sexual HIV transmission. This review seeks to describe the biology of the events leading to HIV infection through the human mucosa and introduce some of the approaches attempted to prevent the sexual transmission of HIV.