Post-transplant lymphoproliferative disorder (PTLD) is a serious and still frequently observed complication of solid organ transplantation. Despite the recent introduction of anti B-cell monoclonal antibody therapy (rituximab) for treatment of PTLD, mortality rates remain high. Because PTLD often presents in a nonspecific way in clinically unsuspected patients, it is a major challenge to diagnose PTLD at an early stage. Epstein-Barr virus (EBV)-DNA load monitoring is a promising tool for the identification of patients at risk for PTLD development. However, there are some limitations of this method, and not all patients at risk for PTLD can be identified by EBV-DNA measurements alone. Therefore, it is of major importance to recognize early clinical signs and symptoms of PTLD. In this review, risk factors for PTLD development, disease presentation, and methods for early detection will be discussed. Special attention is given to allograft and digestive tract localization and the relation with time of onset of PTLD. The value and pitfalls of EBV-DNA load monitoring are discussed. In addition, because fluorodeoxyglucose (FDG)-positron emission tomography (PET) has shown to be a powerful tool for staging and response evaluation of malignant lymphoma, the role of FDG-PET for early diagnosis and staging of PTLD is addressed.