Whether preemptive therapy or universal prophylaxis with ganciclovir is the optimal approach against cytomegalovirus (CMV) remains unresolved. Controversy abounds with respect to the efficacy of preemptive therapy, the reliability of preemptive therapy tools, the logistical difficulties in conducting surveillance monitoring for CMV, the cost of prophylaxis, the effect of prophylaxis on indirect sequelae of CMV and epidemiology of CMV, and the potential for emergence of ganciclovir-resistant CMV. Although neither approach is wholly adequate, a discussion of the relative merits and limitations of the 2 approaches may guide the selection of a rational approach toward prevention of CMV infection in organ transplant recipients.