Respiratory transfusion reactions remain the leading cause of transfusion-related mortality in the United States, according to the most recent data from the US Food and Drug Administration. The pathophysiology of transfusion-related acute lung injury (TRALI) is not fully understood; however TRALI is regarded as the consequence of a two-hit model. The first hit is the clinical condition of the patient with consequent priming of capillaries in the lung. The second hit is the presence in the blood component of human leukocyte antigen (HLA) and/or human neutrophil antigen (HNA) antibodies or proinflammatory mediators present in stored blood components. Because it was recognized that HLA and HNA are more frequently present in female donors with a history of pregnancies, the implementation of mitigation strategies like collecting plasma from male donors has reduced its incidence markedly. However, TRALI still represents the second most common cause of transfusion-associated deaths, highlighting its persistent clinical relevance. TRALI is characterized by the acute onset of noncardiogenic pulmonary edema within 6 h of transfusion and is associated with significant morbidity and mortality. Although advances in donor screening and mitigation strategies have reduced its incidence, TRALI continues to be a diagnostic and therapeutic challenge in critical care and transfusion medicine settings. Early recognition, appropriate supportive care, and implementation of preventive measures remain essential to improving patient outcomes.