The structural versatility of serpins is essential for their inhibitory activity, and the suicide mechanism of inhibition with its large conformational changes and beta-sheet rearrangement are genuinely elegant. However, this structural agility comes at a cost as evidenced by the number of naturally occurring serpin variants that are associated with human disease. In particular, mutations associated with pathologic aggregation and conformational disease arise directly from the serpin need for structural plasticity that is essential for their inhibitory activity. Especially striking in this regard is the observation that in some instances, such as severe anti-trypsin deficiency, the proximal cause of disease is the accumulation of the pathologic aggregates, and not the loss of inhibitor function. This implies that the serpin structure and mechanism must have some evolutionary advantage over the small canonical inhibitors, since if the only relevant function of an inhibitor were blocking proteolytic activity, then the small canonical inhibitors would be very effective without being susceptible to these types of pathologic mutations. However, the wide distribution of serpins and their ability to regulate many different proteases suggests that the serpins provide other benefits to an organism that are not available with the small canonical inhibitors, and that these benefits outweigh the potential disadvantages of the serpin mechanism. The talk will explore this question by examining the importance of serpin interactions with non-protease ligands and by discussing how the serpin inhibitory mechanism regulates these interactions. Possible roles that these associations play in vivo will also be discussed as will their relevance to the development of serpin targeted drugs.