Infections with human cytomegalovirus (HCMV) are a major cause of morbidity and mortality in humans with acquired or developmental deficits in innate and adaptive immunity. In the normal immunocompetent host, symptoms rarely accompany acute infections, although prolonged virus shedding is frequent. Virus persistence is established in all infected individuals and appears to be maintained by both a chronic productive infections as well as latency with restricted viral gene expression. The contributions of the each of these mechanisms to the persistence of this virus in the individual is unknown but frequent virus shedding into the saliva and genitourinary tract likely accounts for the near universal incidence of infection in most populations in the world. The pathogenesis of disease associated with acute HCMV infection is most readily attributable to lytic virus replication and end organ damage either secondary to virus replication and cell death or from host immunological responses that target virus-infected cells. Antiviral agents limit the severity of disease associated with acute HCMV infections, suggesting a requirement for virus replication in clinical syndromes associated with acute infection. End organ disease secondary to unchecked virus replication can be observed in infants infected in utero, allograft recipients receiving potent immunosuppressive agents, and patients with HIV infections that exhibit a loss of adaptive immune function. In contrast, diseases associated with chronic or persistent infections appear in normal individuals and in the allografts of the transplant recipient. The manifestations of these infections appear related to chronic inflammation, but it is unclear if poorly controlled virus replication is necessary for the different phenotypic expressions of disease that are reported in these patients. Although the relationship between HCMV infection and chronic allograft rejection is well known, the mechanisms that account for the role of this virus in graft loss are not well understood. However, the capacity of this virus to persist in the midst of intense inflammation suggests that its persistence could serve as a trigger for the induction of host-vs-graft responses or alternatively host responses to HCMV could contribute to the inflammatory milieu characteristic of chronic allograft rejection.