Transfusion-associated graft-versus-host disease (TA-GVHD) is well recognized as an uncommon, but frequently fatal, adverse effect of blood component therapy. In this disorder, viable donor lymphocytes transfused to a vulnerable patient orchestrate a devastating attack on the recipient's tissues. In contrast to the striking reduction in infectious risks of blood transfusion, a significant residual risk of TA-GVHD remains. This article reviews the pathogenesis and mechanism of TA-GVHD, which provide the foundation for a prevention strategy. A review of selected recent cases illustrates the challenges faced in the identification, prevention, and treatment of this frustrating disorder.