Post transplant lymphoproliferative disorder (PTLD) is a heterogeneous disease that may occur in recipients of solid organ transplants (SOT) and hematopoietic stem cell transplant. The risk of lymphoma is increased 20–120% compared with the general population with risk dependent in part on level of immune suppression. In addition, recent data have emerged, including HLA and cytokine gene polymorphisms, regarding genetic susceptibility to PTLD. Based on morphologic, immunophenotypic, and molecular criteria, PLTD are classified into 4 pathologic categories: early lesions, polymorphic, monomorphic, and classical Hodgkin lymphoma. Evaluation by expert hematopathology is critical in establishing the diagnosis. The aim of therapy for most patients is cure with the concurrent goal of preservation of allograft function. Given the pathologic and clinical heterogeneity of PTLD, treatment is often individualized. A mainstay of therapy remains reduction of immune suppression (RI) with the level of reduction being dependent on several factors (e.g., history of rejection, current dosing, and type of allograft). Outside of early lesions and/or low tumor burden, however, RI alone is associated with cure in a minority of subjects. We approach most newly-diagnosed polymorphic and monomorphic PTLDs similarly using frontline single-agent rituximab (4 weeks followed by abbreviated maintenance) in conjunction with RI. Frontline combination chemotherapy may be warranted for patients with high tumor burden in need of prompt response or following failure of RI and/or rituximab. Due to chemotherapy-related complications in PTLD, especially infectious, we advocate comprehensive supportive care measures. Surgery or radiation may be considered for select patients with early-stage disease. For PTLD subjects with primary CNS lymphoma, we utilize therapeutic paradigms similar to immunocompetent CNS lymphoma using high-dose methotrexate-based therapy with concurrent rituximab therapy and sequential high-dose cytarabine. Finally, novel therapeutic strategies, especially adoptive immunotherapy, should continued to be explored.