Heparin-induced thrombocytopenia (HIT) is arguably the most significant of the drug-induced thrombocytopenias. Two main types of HIT, types I and II, are usually discussed. Type I HIT is characterized by a moderate reduction in platelet counts early in heparin therapy, usually within the first 1 to 3 days. The platelet count rarely drops below 100x10(9)/L and normalizes in spite of continued heparin therapy. Type II HIT is immunologically mediated. The definition of Type II HIT varies, but most studies require a platelet count below 100-150x 10(9)/L for no apparent reason other than heparin administration. Many patients with type II HIT suffer no morbidity. Unfortunately, a significant number, 30 to 60% or more, do develop serious thrombotic complications resulting in morbidity or mortality, including ischemic damage to limbs, central nervous system, myocardium, and lungs. Although earlier literature indicated that arterial thromboses occurred more frequently than venous, recent reports have found that venous thromboses, including deep venous thromboses, pulmonary emboli, and clotted venous catheters, have been common occurrences. In some studies, venous complications were more frequent than arterial. Most investigators have come to believe that these antibodies are largely directed against complexes formed between heparin and the tetrameric PF4. Recent studies devoted to exploring the mechanism by which these antibodies induce platelet activation and thrombosis are discussed.