TRALI is characterized by the accumulation and activation of neutrophils in the pulmonary circulation with subsequent damage to pulmonary endothelial cells and edema. TRALI appears to have multiple mechanisms, the most common being HLA and/or human neutrophil antibodies (HNA) in the plasma of the donor that react with recipient antigens. Because HLA antibodies are frequently stimulated by pregnancy, multiparous women are the most frequently implicated donors. Not all donors with HLA antibodies will cause TRALI in recipients with the corresponding antigens, suggesting that a number of donor and recipient factors must reach a threshold for TRALI to develop (threshold theory). This mechanism involves a two-hit theory in which the first “hit” involves some factor in the recipient that primes neutrophils making them react to a substance in donor plasma (usually HLA or HNA antibodies) inducing a permeability edema. HLA class II antibodies are implicated most frequently but no single specificity seems to be implicated more often than another. Although there appear to be a number of possible mechanisms for TRALI, the majority of severe cases and fatalities have been associated with donor HLA antibodies transfused to patients with the corresponding antigen. HNA antibodies have been reported in >40% of the TRALI cases reviewed and in 12% they were the only antibody present. HNA-3a antibodies have been associated with the most severe forms of HNA-associated TRALI.