A large number of potent and selective therapeutic agents, useful for the treatment of several diseases, have been isolated from natural sources. For example, the most active thrombin inhibitors are those secreted by the salivary glands of leeches. One peculiar feature of these agents is the lack of any significant inhibitory cross-reaction with other serine proteinases. Hence, the knowledge of the exact mechanism of action of these molecules provides the basis for the development of new and efficient synthetic drugs. For this reason, many studies have been undertaken on the structure-activity relationships of natural thrombin inhibitors, and a large amount of detailed information has been obtained by the crystal structures of these inhibitors when complexed with thrombin. In this paper, we review natural and synthetic multisite thrombin inhibitors, whose structural aspects have been determined in detail. We also report here the approach used by us to develop a new class of synthetic, multisite directed thrombin inhibitors, named hirunorms, designed to mimic the distinctive binding mode of hirudin.