Several viral infections, including human immunodeficiency virus, hepatitis B and C viruses, and cytomegalovirus can be transferred from mothers to their infants; these viruses may establish persistent infections and are a significant source of child morbidity and mortality globally. The development of successful preventive antiviral or vaccine strategies is dependent upon better understanding of the infection process and transmitted viral strains, along with defining immune correlates of protection against infection or natural disease. Unique features of MTCT may be particularly helpful in understanding correlates of immune protection. Neonatal vaccination may not only prevent mother-to-child transmission but may also provide lifetime immunity. It is thus also important to define how best to elicit durable protective immune responses in infants.