The development of direct thrombin inhibitors goes back nearly four decades. Organic synthetic benzamidine derivatives were initially developed as direct antithrombin agents. Later, the structural analysis of fibrinogen, leading to the identification of thrombin cleavage sites, resulted in the recognition of specific peptide sequences where thrombin cleaved fibrinogen. These observations led to the development of synthetic peptide derivatives as inhibitors of thrombin. The leech salivary extract contained natural hirudin, the structural elucidation of which led to the development of a recombinant equivalent protein (r-hirudin). Understanding the biochemical actions of thrombin and the structure of various inhibitors prompted the development of hirulogs, a class of hybrid molecules with two sites of action. Currently, several of these thrombin inhibitors are being developed for various indications in both intravenous and subcutaneous protocols. The increased interest in thrombin inhibitors is also prompted by reports of heparin-induced thrombocytopenia (HIT) with heparin and the need to anticoagulate patients with alternate drugs. These agents produce a direct anticoagulant response by targeting thrombin. In addition, the amplification of the coagulation cascade by thrombin activation of factors V and VIII, stabilization of fibrin by activated factor XHI, and platelet activation is also inhibited by these thrombin inhibitors. Some of the synthetic thrombin inhibitors are also capable of inhibiting other enzymes in the coagulation cascade. Thrombin inhibitors therefore exert a complex effect on the coagulation network and should be carefully evaluated in clinical trials. These drugs can be used for prophylactic and therapeutic and surgical indications. However, the different thrombin inhibitors have shown distinct pharmacologic differences. There is now an interest in developing oral antithrombin inhibitors. Such issues as antagonism, laboratory monitoring, drug interactions, and long-term safety remain unresolved. Current research is focused on addressing these issues.