The leading cause of transfusion-related morbidity and mortality in the United States is transfusion-related acute lung injury (TRALI). Diagnostic criteria for TRALI have recently been developed and primarily consist of hypoxia and bilateral pulmonary edema occurring during or within 6 h of a transfusion in the absence of cardiac failure or intravascular volume overload. The primary differential diagnosis is transfusion-associated circulatory overload and differentiation can be difficult. Treatment is supportive with oxygen and mechanical ventilation. Diuresis is not indicated and the role of steroids is unproven. Patients typically recover within a few days. All types of blood products have been associated with TRALI, however, the plasma-rich components, such as fresh frozen plasma and apheresis platelets, have been most frequently implicated. The pathogenesis of TRALI is not completely understood. Leukocyte antibodies in donor plasma have been implicated in most cases with antibodies directed at human leukocyte antigen (HLA) class I, HLA class II or neutrophil-specific antigens, particularly HNA-3a. Activation of pulmonary endothelium is important in the development of TRALI and may account for most cases being observed in surgical or intensive care unit patients. Transfused leukoagglutinating antibodies bind to recipients’ neutrophils localized to pulmonary endothelium resulting in activation and release of oxidases and other damaging biologic response modifiers that cause capillary leak. In a minority of TRALI cases, no antibodies are identified and it is postulated that neutrophil priming factors in the transfused component can mediate TRALI in a patient with pulmonary endothelial activation, the so called “two hit” mechanism. Recognition of the role of anti-leukocyte antibodies has led to new strategies to reduce the risk of TRALI. Female blood donors with a previous pregnancy frequently have HLA antibodies with an overall prevalence of 24% and increasing prevalence related to the number of previous pregnancies. Since HLA antibodies have been implicated in TRALI, blood centers have adopted policies to produce plasma components primarily from male donors. Strategies to reduce the risk from apheresis platelets are problematic and are likely to involve testing female apheresis platelet donors for HLA antibodies. Much more research is needed to understand the blood component and patient risk factors for TRALI so that novel strategies for treatment and additional measures to reduce the risk of TRALI can be developed.