Cytomegalovirus (CMV) is a significant cause of morbidity and mortality following transplantation, especially in the pediatric population, who remain at high risk of primary infection. The availability of effective antiviral therapy has led to dramatic improvements in the outcome of CMV infection in patients undergoing transplantation. In recent years, three major strategies have been developed for the prevention of CMV disease in this population: reduction of risk of viral acquisition or reactivation by management of risk factors; prophylaxis of all 'at-risk' patients using prophylactic strategies for a defined period of time, initiated at or near the time of transplant; and pre-emptive treatment with ganciclovir of selected 'at-risk' patients, guided by either laboratory markers indicative of subclinical infection or the presence of specific risk factors. In general, well designed comparative studies of one or more antiviral agents for the prevention of CMV have not been carried out. While ganciclovir appears to be more effective than aciclovir, its tolerability profile is less optimal. The use of foscarnet avoids myelosuppresions, but is associated with significant nephrotoxicity. Its use should be reserved for patients unable to tolerate ganciclovir or with ganciclovir-resistant CMV disease. Similar to foscarnet, the high frequency of nephrotoxicity associated with the use of cidofovir limits its use to clinical scenarios suggestive of ganciclovir resistance. Newer options, such as valaciclovir and valganciclovir, are currently under investigation and preliminary experience has been promising. Finally, passive immunoprophylaxis has been shown to prevent CMV disease after solid organ transplantation, but its use in bone marrow transplantation is controversial. Essentially, pre-emptive strategies have relied on the quantitation in the peripheral blood of CMV phosphoprotein pp65 antigen and/or the polymerase chain reaction assay. Strict guidelines for the use of those assays as a guide to pre-emptive therapy have not been standardized. Prospective trials comparing pre-emptive therapy using either intravenous or oral ganciclovir, and now oral valganciclovir or valaciclovir, are necessary to determine the relative cost effectiveness and efficacy of these alternative strategies. Finally, it remains controversial as to whether prophylaxis or pre-emptive therapy is the optimal strategy for preventing CMV disease. While a growing body of literature describes these approaches in adult transplant recipients, published experience in children has been much more limited.