Currently available, potent antiviral agents have proven highly effective for the prevention of CMV disease during the time that prophylaxis is employed. However, late-onset CMV disease, occurring in 5–18% of the patients, has emerged as a significant complication in organ transplant recipients receiving prophylaxis. Complete suppression of the virus with long-term use of a potent antiviral agent may be less conducive to antigen-induced priming of host responses, which may explain why there is a greater likelihood of late-onset CMV disease. On the other hand, allowing controlled low-level viral replication, implicit in the strategy of preemptive therapy, may facilitate CMV-specific immune reconstitution and have a mitigating effect on the risk of late-onset CMV disease. Preemptive therapy with valganciclovir appears less likely to be associated with CMV disease, largely due to a lower incidence of late-onset CMV disease. Emerging data, documenting that CMV disease in the era of prophylaxis with potent antiviral agents is an independent contributor to mortality, particularly infection-associated mortality, stands to challenge the notion that prophylaxis is more likely to have a beneficial effect on CMV-related secondary outcomes. Preemptive therapy is a more logical and theoretically more appealing approach for the prevention of CMV disease in transplant recipients. Published in 2006 by John Wiley & Sons, Ltd.