Serpins are a family of serine protease inhibitors that share a unique three dimensional fold containing 3 beta sheets, 8-9 helices and a flexible reactive centre loop (RCL) which acts as the bait for the protease. The inhibition mechanism of serpins involves the initial recognition of the protease followed by the protease cleaving the RCL, concomitant with the conformational change in serpin to form the covalently-linked final serpin-protease complex, where the protease is destroyed due to active site deformation. The native serpin is metastable and contains a 5-stranded beta sheet A, and upon cleavage, RCL inserts into the beta sheet A, resulting in a much more stable 6-stranded form. Work in our lab focus on the serpins in the blood coagulation system, namely antithrombin, heparin cofactor II and protein C inhibitor. Over the past few years, we have solved a number of crystal structures of native serpins and serpin-protease complexes which provide us the molecular insight into how these serpins are activated and how specificity is achieved. In blood, serpins are generally circulating in a state with low activity, with high activity conferred by binding to cofactors at the appropriate time and place. The inhibition specificity can be regulated by interactions in the RCL or exosite through either allostery or bridging.