Thrombin is the central protease in the blood coagulation network. It has multiple substrates and cofactors, and it appears that four serpins are responsible for inhibiting the thrombin produced in haemostasis and thrombosis. Structural studies conducted over the last 10 years have resolved how thrombin recognises these serpins with the aid of cofactors. Although antithrombin (AT), protein C inhibitor (PCI), heparin cofactor II (HCII) and protease nexin-1 (PN1) all share a common fold and mechanism of protease inhibition, they have evolved radically different mechanisms for cofactor-assisted thrombin recognition. This is likely to be due to the varied environments in which thrombin is found. In this review, I discuss the unusual structural features of thrombin that are involved in substrate and cofactor recognition, the serpin mechanism of protease inhibition and the fate of thrombin in the complex, and how the four thrombin-specific serpins exploit the special features of thrombin to accelerate complex formation.