Human cytomegalovirus (HCMV) is a human pathogen that infects greater than 50 % of the human population. HCMV infection is usually asymptomatic in most individuals. That is, primary infection or reactivation of latent virus is generally clinically silent. HCMV infection, however, is associated with significant morbidity and mortality in the immunocompromised and chronic inflammatory diseases in the immunocompetent. In immunocompromised individuals (acquired immune deficiency syndrome and transplant patients, developing children (in utero), and cancer patients undergoing chemotherapy), HCMV infection increases morbidity and mortality. In those individuals with a normal immune system, HCMV infection is also associated with a risk of serious disease, as viral infection is now considered to be a strong risk factor for the development of various vascular diseases and to be associated with some types of tumor development. Intense research is currently being undertaken to better understand the mechanisms of viral pathogenesis that are briefly discussed in this chapter.