Post-transplant lymphoproliferative disorder (PTLD) is a common and serious complication of solid organ transplantation. It is a heterogeneous collection of diagnoses with varied clinical courses and outcomes. The majority of PTLD is Epstein-Barr virus (EBV)-driven as a result of loss of immune control of EBV-positive B lymphocytes. Risk factors for the development of PTLD thus reflect loss or absence of EBV immunity; they include younger age and pre-transplant EBV naivety, as well as the degree and type of immune suppression, type of organ transplantation, and time from transplantation. Identifying patients at risk for PTLD and developing strategies to prevent PTLD is the subject of much research, and the use of antiviral medications and EBV vaccines has yielded intriguing, albeit preliminary, results. As we learn more about the prognostic factors affecting outcome and the pathogenesis of individual diseases, we are better able to tailor therapy to the individual. Further clinical investigation, including randomized controlled trials, will be important in reaching this goal.