Post-transplant lymphoproliferative disorder (PTLD) is an important and potentially life-threatening complication of solid organ transplant (SOT) and hematopoietic stem cell transplant (HSCT). Given the heterogeneity of PTLD and the risk of infectious complications in immunosuppressed patients, treatment of this disease remains challenging. Monomorphic PTLD and lymphoma of B-cell origin account for the majority of cases. Treatment strategies for PTLD consist of response-adapted risk-stratified methods using immunosuppression reduction, immunotherapy, and/or chemotherapy. With this approach, approximately 25% of patients do not need chemotherapy. Outcomes for patients considered high-risk or who do not respond to frontline therapies remain dismal, and novel treatments are needed in this setting. PTLD is associated with Epstein-Barr virus infection in 60-80% of cases making EBV-directed therapy an attractive treatment modality. Recently, the introduction of adoptive immunotherapies represents a promising option for refractory cases; hopefully these treatment strategies can be used in earlier lines of therapy in the future.