Prevention of mother-to-child transmission (PMTCT) of human immunodeficiency virus (HIV) in the United States and Europe has been a tremendous success, such that transmission rates of less than 2% have been achieved. Some key successes have also been demonstrated in resource-poor countries; however, the translation of successful interventions into public health policy has been slow because of a variety of factors such as inadequate funding and cultural, social, and institutional barriers. The issue of HIV and infant feeding in settings that lack culturally acceptable, feasible, affordable, safe, and sustainable nutritional substitutes for breast milk is a continuing dilemma. An effective preventive infant HIV vaccine would be an optimal approach to reduce HIV acquisition in the first year of life among breast-feeding infants. The challenges to eliminate new perinatal HIV infections worldwide will depend on both sustaining and expanding PMTCT interventions and effective primary HIV prevention for women, adolescents, and young adults.