Cytomegalovirus (CMV) remains a cause of significant morbidity and mortality after hematopoietic stem cell transplantation (HSCT). Ganciclovir prophylaxis, or preemptive treatment based on detection of antigenemia or CMV DNA by PCR, effectively prevents CMV disease during the first 100 days after transplant in allograft recipients. In recipients of T-cell depleted transplant or if severe acute graft-versus-host disease is present, ganciclovir prophylaxis or preemptive treatment should be started with an induction course of ganciclovir (5 mg/kg BID) and given at least 5 days per week and continued until day 100 after transplant. Although prevention of CMV disease before day 100 is highly effective, there is a continued risk of late-onset CMV disease after day 100. In CMV-seropositive recipients, the incidence of late CMV disease may be as high as 17%. Strategies to prevent late CMV infection and disease are needed. In seronegative recipients, seronegative or leukocyte-reduced blood products are effective in preventing acquisition of CMV through blood products. Controversy exists about the optimal strategy of preventing CMV disease in seropositive autologous HSCT recipients. The outcome of CMV pneumonia remains poor despite treatment with ganciclovir in combination with CMV hyperimmune globulin or intravenous immunoglobulin. Owing to continued clinical significance of CMV in the HSCT setting, new and more effective anti-CMV drugs with improved pharmacokinetic properties are urgently needed.