One of the most common clinical sequelae of massive transfusion is acute lung injury. In virtually all clinical settings, there is a very strong relationship between transfusion and acute lung injury that remains even after adjusting for potential confounders. Whether the association between transfusion and acute lung injury in these settings is a result of residual confounding or actually reflects a causal relationship is unknown. However, there are several potential mechanisms by which massive transfusion might predispose to lung injury: a) cognate antigen-antibody interactions (classic transfusion-associated lung injury); b) activation of nonspecific immunity through soluble mediators present in transfused blood; c) an increased risk of infection through transfusion-associated immunomodulation leading to sepsis and sepsis-induced lung injury; and d) volume overload in the face of increased permeability of the alveolar capillary membrane. Elucidating the precise causal mechanism operative in patients receiving massive transfusion has more than academic importance; it has direct implications for transfusion policy and practice.