The native fold of inhibitory serpins (serpin proteinase inhibitors) is metastable and therefore does not represent the most stable conformation that the primary sequence encodes for. The most stable form is adopted when the reactive centre loop (RCL) inserts, as the fourth strand, into the A β-sheet. Currently a serpin can adopt at least four more stable conformations, termed the cleaved, delta, latent and polymeric states. The accessibility of these alternative low energy folds renders the serpin molecule susceptible to mutations that can result in dysfunction and pathology. Here, we discuss the means by which the serpin can attain and preserve this metastable conformation. We also consider the triggers for misfolding to these more stable states and the mechanisms by which it occurs.