There are no apparent biologic obstacles to immunization against fetal/placental infection with cytomegalovirus (CMV), and vaccine candidates have been developed. The major obstacles for a human CMV vaccine are difficulties associated with the design and execution of efficacy trials. These trials will be prolonged with difficulties in recruiting subjects, and hampered by several factors: First is a lack of public awareness of CMV, making recruitment into vaccine trials difficult. Second is that trials using fetal infection as an endpoint will be prolonged since vaccine administration must occur preconception. Third, behavioral changes by subjects will affect infection rates, and controls for behavioral changes will have to be in place in any clinical trial. Fourth, not all women are at equal risk for CMV infections. High risk women may become infected by contact with young children or via sexual activity. Thus, the mode of acquisition may be a confounding variable in vaccine efficacy trials. In spite of these potential obstacles, successful evaluation of CMV vaccines is possible and likely when considered against similar obstacles encountered by several other recently licensed vaccines.