Congenital human cytomegalovirus (HCMV) infection is the leading infectious cause of mental retardation and sensorineural deafness. Intrauterine transmission and adverse outcome are mainly related to primary maternal infection. Mechanisms of intrauterine transmission are slowly being unraveled and compelling evidence of the importance of using HCMV clinical strains rather than laboratory-adapted strains for in vitro studies is growing. In the absence of a vaccine or a specific antiviral therapy which could be safely administered to pregnant women with primary HCMV infection, the option of prenatal diagnosis has a crucial role in the management of pregnancy complicated by primary HCMV infection. Reliability of prenatal results, however, is still a major concern presenting the risk of either false-negative or false-positive results. However, as more light is shed on the natural history of HCMV infection during pregnancy and fetal life, the predictive value of negative prenatal diagnosis results is becoming more defined, thus improving the quality of counseling. In addition, the availability of different assays for detection of HCMV in both fetal blood and amniotic fluid samples will eventually reduce the risk of false-positive results. Finally, the identification of reliable prognostic markers of fetal disease remains the ultimate goal and a major challenge.