The aim of this review is to explain the central role of thrombin in haemostasis and the main pharmacological features of the anticoagulants that are direct inhibitors of thrombin, with emphasis on orally active small molecules. Owing to the complexity of the clotting system only well designed and conducted studies can tell us which drug is the most useful, safe and convenient to limit each type of thrombosis and what are the appropriate dosage and management. Parenterally administered direct thrombin inhibitors require laboratory monitoring, whereas dabigatran, orally active, does not.