This chapter provides an algorithmic approach for the clinical management and laboratory investigation of transfusion reactions. Acute transfusion reactions can usually be placed into some of the following categories: acute haemolysis (AHTR); transfusion‐related acute lung injury (TRALI); and febrile nonhaemolytic reactions (FNHTR). There are other types of reactions that can occur following the acute period, including delayed haemolytic reactions, transfusion‐ associated graft‐versus‐host disease, posttransfusion purpura, alloimmune thrombocytopenia and alloimmune neutropenia. 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. The chapter summarizes some considerations to assist in the decision‐making process. The volume of the component transfused can be an important consideration for a differential diagnosis.