Cytomegalovirus (CMV) is one of the most important pathogens following solid-organ transplantation, and effective prevention of CMV infection is a priority. The long-term control of CMV infection is dependent, in part, on the development of CMV-specific T cells, and controversy exists regarding whether CMV prophylaxis may prevent this. Although preemptive therapy is beneficial for the prevention of CMV disease, monitoring of viral levels in the blood does not always reflect what is occurring in tissues. Persistent low-level CMV infection has been associated with indirect consequences, such as transplant-associated vasculopathy, posttransplantation diabetes, an increased risk of opportunistic infection, and graft rejection. The issues surrounding preventive strategies for CMV disease following solid-organ transplantation are reviewed. We argue that prophylaxis is more effective than preemptive therapy; extending the duration of prophylaxis to the period of less intense immunosuppression could protect patients from late-onset disease, as well as from the indirect effects of CMV infection.