Transfusion-associated circulatory overload (TACO) and transfusion-related acute lung injury (TRALI) are syndromes of acute respiratory distress that occur within 6 hours of blood transfusion. TACO and TRALI are the leading causes of transfusion-related fatalities, and specific therapies are unavailable. Diagnostically, it remains very challenging to distinguish TACO and TRALI from underlying causes of lung injury and/or fluid overload as well as from each other. TACO is characterized by pulmonary hydrostatic (cardiogenic) edema, whereas TRALI presents as pulmonary permeability edema (noncardiogenic). The pathophysiology of both syndromes is complex and incompletely understood. A 2-hit model is generally assumed to underlie TACO and TRALI disease pathology, where the first hit represents the clinical condition of the patient and the second hit is conveyed by the transfusion product. In TACO, cardiac or renal impairment and positive fluid balance appear first hits, whereas suboptimal fluid management or other components in the transfused product may enable the second hit. Remarkably, other factors beyond volume play a role in TACO. In TRALI, the first hit can, for example, be represented by inflammation, whereas the second hit is assumed to be caused by antileukocyte antibodies or biological response modifiers (eg, lipids). In this review, we provide an up-to-date overview of TACO and TRALI regarding clinical definitions, diagnostic strategies, pathophysiological mechanisms, and potential therapies. More research is required to better understand TACO and TRALI pathophysiology, and more biomarker studies are warranted. Collectively, this may result in improved diagnostics and development of therapeutic approaches for these life-threatening transfusion reactions.