Most HIV infections worldwide are transmitted through heterosexual contact. In order to develop vaccination strategies, the basic biology of the immune system in female reproductive tract and the full range of vaginal immune responses that occur during natural HIV infection must be understood. The cervicovaginal mucosa contains a complete set of immune cells, including antigen-presenting cells, CD4+ and CD8+ T cells, and B cells. The CVS of HIV-infected women and SIV-infected female rhesus macaques contain variable levels of antiviral antibodies. Some of this variation is due to the effects of female ovarian hormone cycle. IgG antibodies make up the bulk of the antiviral antibody response. However, IgA antibodies are present at lower levels. HIV/SIV-specific CD8+ cytotoxic T lymphocytes are present in the cervicovaginal mucosa of infected women and rhesus macaques. A vaccine that can elicit strong antiviral immunity may provide protection for hetorosexual HIV-1 transmission.