Heparin-induced thrombocytopenia (HIT) is the most common, immune-mediated adverse drug reaction affecting blood cells. It is of high clinical relevance, as in patients developing this immune response, the anticoagulant heparin becomes prothrombotic. The pathogenesis of the prothrombotic effects of HIT has been largely resolved, and alternative anticoagulants are available to treat affected patients. However, the immune mechanisms underlying HIT are still unclear. HIT is likely a misdirected host defense mechanism against bacteria, indicating that platelet factor 4, the key antigen in HIT, when complexed to heparin, has a role in bridging innate and adaptive immunity. Laboratory diagnosis of HIT is still a major challenge. Only a subgroup of patients developing anti-PF4/heparin antibodies also develops HIT. The chapter summarizes current concepts of the pathogenesis and treatment of HIT as well as approaches to diagnose HIT.KeywordsHeparin, platelets, PF4, thrombosis, laboratory diagnosis, PF4/heparin enzyme immunoassay, serotonin release assay, HIPA test, hirudin, danaparoid, argatroban, bivalirudin, fondaparinux.