In this chapter, an algorithmic approach is provided for the clinical management and laboratory investigation of transfusion reactions. Acute reactions can usually be placed into the following categories: acute haemolysis, allergic, anaphylactic, transfusionârelated acute lung injury, and acute pain reaction. The clinician must make a decision whether to stop the administration of the blood component temporarily or discontinue the transfusion, and must decide the extent of the investigations to be performed. To ensure management strategies and investigations that minimise risks to patients, healthcare professionals need to understand the aetiology and pathophysiology of each type of acute reaction. It is also essential to understand the typical clinical presentation for each type of reaction so that a differential diagnosis can be formulated as part of the investigative process. Some clinical judgement is required when deciding which reactions to investigate more fully and the management strategies required.