The SIV/Rhesus macaque model of HIV transmission has led to an increased understanding of the interactions between virus and host during the sexual transmission of HIV. SIV can be transmitted across the intact mucosa (stratified squamous epithelium) of the foreskin and glans of the penis of Rhesus macaques. SIV-infected cells can be found at all levels of the male Rhesus macaque reproductive tract and SIV can infect cells in the mucosal epithelium of the foreskin of the penis. SIV can be transmitted to female Rhesus macaques by infusing a cell-free virus suspension into the vaginal canal through a soft plastic pediatric nasogastric feeding tube. There does not appear to be any correlation between inoculation at any particular point in the menstrual cycle and the susceptibility of an animal to infection. Furthermore, the surgical removal of the cervix and uterus did not affect the dose of cell-free virus required for the genital transmission of SIV. Thus, target cells for SIV are present in the vaginal mucosa. In chronically-infected female Rhesus macaques, SIV-infected cells are present in the uterus, cervix and vagina. SIV-infected CD1a+ and p55+ Langerhans cells are also found within the stratified squamous epithelium of the vagina. Taken together these results are consistent with the hypothesis that the virus initially infects antigen-presenting cells in the vagina (macrophages and Langerhans cells) and then subsequent rounds of replication occur in the draining lymph nodes prior to spreading to more proximal lymphoid nodes and finally to the bloodstream and distant lymphoid tissue.