Although infection with human cytomegalovirus (HCMV) is ubiquitous and usually asymptomatic, there are individuals at high risk for serious HCMV disease. These include solid organ and hematopoietic stem cell (HSC) transplant patients, individuals with HIV infection, and the fetus. Since immunity to HCMV ameliorates the severity of disease, there have been efforts made for over 30 years to develop vaccines for use in these high-risk settings. However, in spite of these efforts, no HCMV vaccine appears to be approaching imminent licensure. The reasons for the failure to achieve the goal of a licensed HCMV vaccine are complex, but several key problems stand out. First, the host immune correlates of protective immunity are not yet clear. Secondly, the viral proteins that should be included in a HCMV vaccine are uncertain. Third, clinical trials have largely focused on immunocompromised patients, a population that may not be relevant to the problem of protection of the fetus against congenital infection. Fourth, the ultimate target population for HCMV vaccination remains unclear. Finally, and most importantly, there has been insufficient education about the problem of HCMV infection, particularly among women of child-bearing age and in the lay public. This review considers the strategies that have been explored to date in development of HCMV vaccines, and summarizes both active clinical trials as well as novel technologies that merit future consideration toward the goal of prevention of this significant public health problem.