Studies to examine the mechanisms responsible for perinatal HIV transmission and clinical trials to reduce this transmission are ongoing. A more complete understanding of the timing and modalities of vertical transmission will permit more precise targeting of future clinical trials. Perinatal transmission of HIV infection is most likely due to multiple factors. The degree of viral replication, neutralizing antibody and other maternal immune factors, genetic factors, and an intact placental barrier are most likely important and may be interrelated. Multiple different combination therapies may be necessary to interrupt maternal-fetal HIV transmission. Pregnancy is a well-defined and limited time period, and offers a model for HIV transmission where clinical, virological, and immunological factors can be evaluated in relation to the occurrence of HIV infection in the infant. The analysis of perinatal trials may provide insight into factors involved in protection and have implications. As HIV infection rates in the heterosexual populations of US inner cities and in impoverished areas of the third world continue to rise rapidly, strategies are needed urgently to curb the AIDS epidemic in children. Targeting the HIV-infected pregnant woman for therapies is one of the few hopes we have of preventing infection in children at risk of HIV infection. Without such therapeutic strategies, many of these at-risk infants are destined to acquire a chronic viral infection with significant morbidity and mortality.