Allogeneic hematopoietic cell transplantation (allo-HCT) may prolong life and cure patients suffering from otherwise fatal diseases. However, the growing population of long-term survivors has led to the realization of multiple long-term complications, including the risk of second malignancies. Compared to the autologous setting, allo-HCT carries a much higher risk of posttransplant lymphoproliferative disorder (PTLD), which usually occurs within the first year after allo-HCT and is strongly associated with the Epstein-Barr virus (EBV). Treatment-related myelodysplastic syndromes (tMDS) and second leukemias are extremely rare. Both autologous and allo-HCT carry increased risks for second solid malignancies (SSM). The cumulative incidence of SSM continues to increase in each of the largest studies with as much as 20 years of follow-up, likely related to the long latency of radiation-related SSM. Systematic, prospective monitoring, vigilant screening processes, and well-maintained survivorship clinics and databases are absolute necessities, and should be included in the infrastructure of individual transplant centers and networks, with mandatory periodic reporting of second malignancy incidences. Primary care and transplant physicians alike must be aware of the risk of second malignancies after allo-HCT. Most importantly, guidelines should be developed in regard to screening and prevention of second malignancies, so that physicians can provide state-of-the-art counsel and care for the benefit of our patients. © 2007 American Society for Blood and Marrow Transplantation.