Transfusion-related acute lung injury (TRALI) is a life-threatening adverse event in blood transfusion and is considered the most common cause of transfusion-related fatalities in the United States and the United Kingdom. TRALI and acute respiratory distress syndrome (ARDS) share a common clinical definition except that TRALI is temporally and mechanistically related to blood transfusion. Two different mechanisms have been proposed. The first is leuko-agglutination due to infusion of leukocyte Antibodies with the blood product transfused. The second proposes a two-event model where the first event is the clinical condition of the patient, and the second the infusion of lipids that accumulate in blood products during storage. An emerging common pathway of granulocyte activation is discussed, as is the relevance of immune and non-immune TRALI from a practical point of view. Some unresolved questions in TRALI pathophysiology, including the relevance of Antibodies to HLA class-II antigens and the participation of the endothelium, are examined, as are the suggested preventive measures for both immune and non-immune TRALI. It is concluded that further clinical and experimental data are necessary before any recommendations can be made regarding non-immune TRALI. In contrast, in immune TRALI, preventive measures to avoid transfusion of blood products that contain leukocyte Antibodies should be taken now.