Transfusion-related acute lung injury (TRALI) has been the leading cause of transfusion-related deaths reported to the United States Food and Drug Administration for three consecutive years. Although traditionally TRALI has been viewed as having a one event pathogenesis (passive donor anti-leukocyte antibody interacting with a cognate antigen on the recipients leukocytes), emerging evidence suggests that TRALI is a multifactorial syndrome, and a true two-event subtype of ALI. Both recipient predisposition and biological response modifiers, generated during storage of cellular blood products, appear to play major pathogenetic roles. This review highlights recent advances in our knowledge of the pathophysiology of TRALI and recent progress towards a consensus definition of TRALI. It also guides the reader as to the recognition, investigation, and clinical management of TRALI.