Human cytomegalovirus (HCMV) disease is a major cause of morbidity and mortality in neonates and immunocompromised populations, such as transplant recipients and HIV-infected patients. The development of a vaccine to prevent HCMV infection or disease has been assigned the highest priority by the US Institute of Medicine. Although, after 30 years of intensive study, a clinically licensed vaccine is still not available, significant progress has been made in the field of HCMV vaccine development, along with greater understanding of HCMV immunology, molecular biology and pathology. In recent years, new vaccine strategies have been developed that have shown promising results in preclinical studies and are able to induce HCMV-specific immune responses in clinical studies, although efficacy data are not yet available. Here we review the history of HCMV vaccine development and the current strategies in the development of new HCMV vaccines. We propose that research should focus on the development of a vaccine to prevent or control HCMV-related disease rather than to prevent infection, and that discerning strategies should be used for targeting HCMV disease in different clinical settings.