A brief overview of the pathophysiology, diagnosis, and treatment of heparin-induced thrombocytopenia (HIT) is discussed. Following any exposure to unfractionated heparin or low-molecular-weight heparin (LMWH), HIT, a serious allergic drug reaction, may occur. The frequency of HIT is thought to range from 1 to 5% of patients receiving heparin. This immune-mediated syndrome is paradoxically associated with thrombosis, not bleeding, with thrombin generation playing a central role. The diagnosis of HIT is based upon clinical findings that can be confirmed with laboratory assay; however, when there is clinical suspicion of HIT, all forms of heparin therapy should be immediately discontinued and initiation of alternative anticoagulation is strongly encouraged. In the presence of HIT, the use of LMWHs or initiation of warfarin without additional effective anticoagulation is not recommended. Argatroban and lepirudin, two direct thrombin inhibitors (DTIs), are approved by the Food and Drug Administration for the management of HIT. Both agents have been studied in the treatment and prevention of thrombotic events associated with HIT. Argatroban, a univalent inhibitor of thrombin, is eliminated via the liver, while lepirudin, the first DTI approved for HIT, is a bivalent thrombin inhibitor that is cleared by the kidneys. Neither argatroban nor lepirudin demonstrates cross-reactivity with heparin-induced antibodies, and both DTIs have been associated with effective anticoagulation and platelet recovery in patients with HIT. The appropriate use of DTIs in HIT reduces the risk of thrombotic events and severe consequences associated with this serious drug reaction.