Small-molecule direct thrombin inhibitors represent a new class of anticoagulants and are emerging as antithrombotic drugs with a range of indications. The tripeptide type or peptidomimetic compounds, including argatroban, efegatran, inogatran and napsagatran, hitherto clinically studied represent a first generation of thrombin inhibitors that are pharmacokinetically characterised by relatively rapid hepato-biliary clearance and short half-lives necessitating their administration as intravenous infusion. They are not orally bioavailable because of poor enteral absorption and presystemic hepatic extraction. Melagatran can be administered subcutaneously, and a prodrug form of melagatran, ximelagatran, is at present the only oral thrombin inhibitor available. Direct thrombin inhibitors produce predictable, stable and rapidly reversible anticoagulation measurable by common coagulation assays. Significant pharmacokinetic drug-drug interactions have not been reported. Possible pharmacodynamic interactions, in terms of prolongation of plasma clotting times, with other anticoagulant drugs must be taken into account when monitoring direct thrombin inhibitors using coagulation assays.