Post-transplant lymphoproliferative disorder (PTLD) represents a heterogeneous group of abnormal lymphoid proliferations, generally of B-cells, that occur in the setting of ineffective T-cell function because of pharmacological immunosuppression after organ transplantation. The vast majority of PTLDs are associated with Epstein-Barr virus (EBV) infection, as manifested by the presence of EBV within the malignant tissue. Surveillance for the presence of primary or reactivated EBV infection may have the potential to prevent the development of PTLD by early intervention. However, there are, at present, no means of discriminating between innocent infectious mononucleosis syndromes and PTLD. Furthermore, standardization of measurement of EBV copies between centers is urgently required for the definition of "high" EBV viral load. Because of a lack of a close relationship between viral load and the occurrence of PTLD, other strategies such as the combined analysis of EBV viral load and EBV-specific T-lymphocytes may be better to assess the risk for the development of PTLD. Whereas the mainstay of therapy for overt PTLD is reduction of immunosuppression, such reduction based solely on a high EBV viral load without clinical evidence for PTLD is not based on scientific evidence. This strategy could result in the under-immunosuppression of many transplant recipients in the absence of a real risk for PTLD, with potentially harmful consequences such as an increased rate of acute rejection episodes.