Heparin-induced thrombocytopenia (HIT) is a prothrombotic disorder that paradoxically is caused by the widely used anticoagulants, heparin and (less often) low molecular weight heparin. HIT results when multimolecular complexes formed by (polyanionic) heparin and (polycationic) platelet factor 4 (PF4) result in antibodies, mainly of the IgG class, that recognize antigens on PF4, thereby forming PF4/heparin/IgG complexes that activate platelets, monocytes, and neutrophils via their Fcγ receptors. Classic HIT (cHIT), which features antibodies that predominantly recognize heparin-dependent antigens on PF4, represents the prototypic anti-PF4 disorder. A more severe subtype of HIT with an atypical clinical presentation (“atypical” or “autoimmune” HIT [aHIT]) features highly pathogenic antibodies with additional heparin-independent platelet-activating properties. Rarely, a disorder clinically and serologically indistinguishable from HIT occurs in the absence of proximate heparin exposure (“spontaneous HIT” [SpHIT]). HIT is by far the most common immune-mediated adverse drug reaction that affects blood cells. This chapter addresses the clinical presentation and laboratory diagnosis of HIT and summarizes recent findings on its pathogenesis, including the concept that HIT is likely a misdirected bacterial host-defense mechanism. Basic aspects of HIT treatment are briefly summarized.