Human cytomegalovirus is the most common congenital viral infection in humans, with a reported annual incidence of approximately 1% in the United States and Western Europe. An estimated 10% of congenitally infected babies will exhibit symptoms of intrauterine HCMV infection at delivery, and over 60% of these babies will manifest permanent CNS developmental abnormalities. Currently, congenital HCMV is the most common infectious aetiology of brain damage in newborn infants in the United States. Common presentations in the newborn period include hepatobiliary disease, thrombocytopenia, and evidence of CNS damage. Long-term neurodevelopmental sequelae range from severe psychomotor retardation to hearing deficits. Maternal primary infection during pregnancy represents a significant risk for transmission and disease in the developing fetus. Numerous natural history studies have provided clear evidence of the importance of preconceptional maternal sero-immunity in the prevention of fetal infection as well as limiting damage in infected fetuses. Sources of maternal exposure to HCMV include sexual activity and exposure to young children infected with HCMV. Attempts to limit exposure have been hampered by the persistent excretion of HCMV in infected children and the silent nature of the infection in sexual partners. Protective immunity can be documented, suggesting that this is a vaccine-modifiable disease. Candidate vaccines have been formulated, and in some cases appear to induce immunity similar to that observed following natural infection.