Transfusion-related acute lung injury (TRALI) is a life-threatening adverse event of transfusion, which has an increasing incidence in the United States and is the leading cause of transfusion-related death. TRALI and acute lung injury (ALI) share a common clinical definition except that TRALI is temporally- and mechanistically-related to transfusion of blood or blood components. A number of different models have been proposed to explain the pathogenesis. The first is an antibody-mediated event whereby transfusion of anti-HLA, class I or class II, or anti-granulocyte antibodies into patients whose leukocytes express the cognate antigens. The antibody:antigen interaction causes complement-mediated pulmonary sequestration and activation of neutrophils (PMNs) resulting in TRALI. The second is a two-event model: the first event is the clinical condition of the patient resulting in pulmonary endothelial activation and PMN sequestration, and the second event is the transfusion of a biologic response modifier (including anti-granulocyte antibodies, lipids, and CD40 ligand) that activates these adherent PMNs resulting in endothelial damage, capillary leak, and TRALI. These hypotheses are discussed with respect to animal models and human studies that provide the experimental and clinical relevance. The definition of TRALI, patient predisposition, treatment, prevention and reporting guidelines are also examined.