The central role of the serine protease thrombin in hemostasis and thrombosis brought many scientists to develop highly potent and selective thrombin inhibitors. Thrombin-inhibitor complexes have extensively been studied in order to understand structure-function relationships, and to design new inhibitors that can be used with broader efficacy over existing antithrombotic agents. In this paper, we summarize in a comparative manner the state of the art on reversible thrombin inhibitors and we discuss some structural aspects of thrombin-inhibitor interaction, which account for the different affinity and potency of these molecules. We also report here our approach to develop a new class of synthetic, multisite-directed thrombin inhibitors, named hirunorms, designed to mimic the distinctive binding mode of hirudin. We emphasize here that, despite the high specificity of thrombin action, the interaction of inhibitors in its active site may occur with quite different mechanisms.