Increased availability of antiretroviral therapy to pregnant and breastfeeding women in resource-limited areas has proven remarkably successful at reducing HIV vertical transmission rates over the past several decades. Yet, still more than 170,000 children are infected annually due to failures in therapy implementation, monitoring, and adherence. Mother-to-child transmission (MTCT) of HIV-1 can occur at one of several distinct stages of infant development - intrauterine, intrapartum, and postpartum. The heterogeneity of the maternal-fetal interface at each of these modes of transmission poses a challenge for the implementation of immune interventions to prevent all modes of HIV MTCT. However, using mother-infant human cohorts and nonhuman primate models of infant simian immunodeficiency virus (SIV) acquisition, investigators have made important observation about the biology of pediatric HIV infection and have identified unique protective immune factors for each mode of transmission. Knowledge of immune factors protective against HIV MTCT will be critical to the development of targeted immune therapies to prevent infant HIV acquisition and to bring an end to the pediatric AIDS epidemic.