Despite advances in prophylaxis and treatment, cytomegalovirus (CMV) infection remains a significant problem in the solid-organ transplant recipient. In addition to the clinical manifestations of CMV infection, there is also the immunosuppressive effect of CMV, which confers increased risk for fungal and other opportunistic infections. In reference to heart transplant recipients, the possible connection between CMV infection and rejection or CMV infection and allograft vasculopathy are areas of active research. Recent diagnostic advances, such as the CMV antigenemia assay and CMV-DNA detection by polymerase chain reaction or direct hybrid capture, have enabled early detection and monitoring of CMV infection and have raised the question of the implications of asymptomatic viremia. A wide variety of prophylactic strategies have been evaluated in heart and other solid-organ transplant recipients, including antiviral agents, globulin preparations, combinations of these therapies, and pre-emptive treatment strategies based on early detection or identification of a high-risk subset of patients. Many of these regimens have demonstrated efficacy in certain groups of patients, but a consensus has yet to emerge in terms of a single preferable strategy. Future advances on the horizon include the development of newer antiviral agents and a vaccine.