CMV is one of the most frequent viral infections after orthotopic liver transplantation. Thus, there should be a high index of clinical suspicion, particularly in liver transplant recipients who have risk factors for the development of CMV disease, including donor CMV seropositivity, the use of antilymphocyte preparations, and retransplantation. The availability of effective antiviral therapy to treat CMV disease has emphasized the importance of an aggressive approach to the early diagnosis and treatment of this viral infection. Ganciclovir has been a major advancement in the treatment of severe CMV disease and has had a major impact on reducing the incidence and severity of CMV disease and its complications in the liver transplant recipient. Furthermore, these antiviral agents are now being evaluated for their prophylactic potential. Indeed, a number of these agents or combinations of these agents have been shown to be effective in reducing the incidence and severity of CMV disease, particularly in the CMV-seropositive transplant recipient; however, the cost-effectiveness of such therapy and its overall impact on long-term graft and patient outcome remain poorly defined at this time. Further investigations will be needed to define the role and importance of prophylactic therapy for the prevention of CMV infection and disease in the liver transplant recipient.