Heparin-induced thrombocytopenia (HIT) is caused by IgG antibodies that recognize platelet factor 4 (PF4) bound to heparin or certain other polyanions. Although many heparin-exposed patients form nonpathogenic anti-PF4/heparin antibodies, pathologic antibodies capable of triggering HIT activate platelets via their FcγIIa receptors. HIT is strongly associated with thrombosis, both venous and arterial. Approximately 5% of patients develop limb ischemic necrosis due to arterial thrombosis or even venous limb gangrene. HIT usually causes moderate thrombocytopenia: the median platelet count nadir is 60×109/L, and only 5% of patients have a platelet count 15×109/L. Bleeding is uncommon; indeed, adrenal hemorrhage complicating HIT is caused by adrenal vein thrombosis (with secondary hemorrhage). HIT has characteristic timing: the platelet count usually begins to fall 5 to 10 days after an immunizing heparin exposure (typical-onset HIT); however, an abrupt platelet count fall can occur (rapid-onset HIT) when heparin is restarted in a patient who already has circulating HIT antibodies. “Autoimmune HIT” is explained by antibodies that activate platelets in both heparin-dependent and heparin-independent fashion; associated syndromes include delayed-onset HIT (thrombocytopenia that begins or worsens after stopping heparin) and spontaneous HIT syndrome (clinical/serological picture of HIT without proximate heparin exposure). HIT presents numerous treatment paradoxes, including high risk of microthrombosis/limb gangrene with warfarin treatment (hence, vitamin K antagonism is contraindicated during acute thrombocytopenia) and frequent failure of PTT-adjusted anticoagulant therapy of severe HIT complicated by disseminated intravascular coagulation (“PTT confounding”). The author advocates treating HIT with non–PTT-adjusted therapies such as fondaparinux and even direct oral anticoagulants (e.g., rivaroxaban).