Prevention of cytomegalovirus (CMV) infection after hematopoietic stem cell transplantation (HSCT) generally involves preemptive treatment of recognized infection before the onset of overt CMV-associated disease. The success of this method depends on efficient recognition of infection and intervention before the disease progresses. Reliable tests for such diagnosis include blood culture, antigenemia assays, polymerase chain reaction assays, and other DNA sequence- or RNA sequence-based assays. For selected high-risk patients, such as patients receiving T cell-depleted hematopoietic stem cell transplants, prophylactic use of antiviral agents before the onset of CMV infection is recommended. The ability to monitor the immunological status of the patient relative to CMV-specific immunity is increasing in importance. Ultimately, the solution to the problem of efficient prevention of CMV infection in this population will require combined antiviral chemotherapy and improved reconstitution of CMV immunity.