The development of prophylactic and to lesser extent therapeutic vaccines for the prevention of disease associated with human cytomegalovirus (HCMV) infections has received considerable attention from biomedical researchers and pharmaceutical companies over the previous 15 years, even though attempts to produce such vaccines have been described in the literature for over 40 years. Studies of the natural history of congenital HCMV infection and infection in allograft recipients have suggested that prophylaxis of disease associated with HCMV infection could be possible, particularly in hosts at risk for more severe disease secondary to the lack of preexisting immunity. Provided a substantial understanding of immune response to HCMV together with several animal models that faithfully recapitulate aspects of human infection and immunity, investigators seem well positioned to design and test candidate vaccines. Yet more recent studies of the role of a maternal immunity in the natural history of congenital HCMV infection, including the recognition that reinfection of previously immune women by genetically distinct strains of HCMV occur in populations with a high seroprevalence, have raised several questions about the nature of protective immunity in maternal populations. This finding coupled with observations that have documented a signifi cant incidence of damaging congenital infections in offspring of women with immunity to HCMV prior to conception has suggested that vaccine development based on conventional paradigms of adaptive immunity to viral infections may be of limited value in the prevention of damaging congenital HCMV infections. Perhaps a more achievable goal will be prophylactic vaccines to modify HCMV associated disease in allograft transplant recipients. Although recent descriptions of the results from vaccine trials have been heralded as evidence of an emerging success in the quest for a HCMV vaccine, careful analyses of these studies have also revealed that major hurdles remain to be addressed by current strategies.