Cytomegalovirus is a significant cause of morbidity and mortality in transplantation. Controversy exists concerning whether prophylactic or pre-emptive therapy is the optimal strategy for preventing CMV disease. In addition, CMV impacts the transplanted graft, transplant recipient and transplant programme beyond just causing CMV disease; thus questioning whether ‘asymptomatic’ CMV replication should also be prevented. In this Forum article, prophylactic therapy is advocated as the preferred approach for preventing CMV disease. Prophylactic therapy has a large body of supportive controlled clinical studies demonstrating its efficacy and cost effectiveness. In addition, prophylactic therapy has the benefit of preventing other herpes viruses and other opportunistic superinfections by reducing the immunosuppressive effects of CMV. Moreover, a small but growing body of information suggests that prophylactic therapy may also have a beneficial effect on organ outcomes, including rejection. In contrast, pre-emptive therapy is limited by its reliance on intensive surveillance, which presents logistical difficulties and requires perfect patient compliance. Ambiguity still exists concerning the best surveillance method and its effect on patient-care costs. Each proposed diagnostic approach has limitations, which are affected by the prevalence of CMV in the population studied, the particular assay employed, and the frequency of surveillance. The suggested benefits of pre-emptive therapy, such as decreased cost, fewer adverse medication effects and less antiviral resistance have not been adequately proven in head-to-head clinical studies. We therefore support the proposition that transplant patients at risk for any level of CMV replication will significantly benefit from effective antiviral prophylaxis. Copyright © 2001 John Wiley & Sons, Ltd.