A functional abnormality of C1 inhibitor (C1INH) is present in types I and II hereditary angioedema (HAE), and normal C1INH may be rendered ineffective in the newly described type III HAE. C1INH inhibits factor XIIa, factor XII fragment (XIIf), kallikrein, and plasmin. Thus, in its absence, there is marked activation of the bradykinin-forming cascade resulting in severe angioedema. Factor XII may autoactivate on binding to endothelial cell surface gC1qR (receptor for the globular heads of C1q) thus initiating the cascade. Alternatively, stimuli that activate endothelial cells may liberate (or express at the cell surface) heat shock protein 90 or the enzyme prolylcarboxypeptidase, either of which can interact with the prekallikrein-high-molecular-weight kininogen complex to convert prekallikrein to kallikrein stoichiometrically. The kallikrein produced can cleave high-molecular-weight kininogen to produce bradykinin and also recruit factor XII by enzymatically activating it. Patients with type I or II HAE have mutant C1INH so that control of C1 activation is lost. Autoactivation of C1r in the absence of C1INH leads to C1s activation followed by C4 cleavage and depletion. An attack of swelling is accompanied by conversion of factor XIIa to factor XIIf and further enzymatic activation of C1r so that C4 levels drop further and C2 is depleted. New therapies for HAE focus on the bradykinin-forming cascade and include a kallikrein inhibitor and a bradykinin B-2 receptor antagonist in addition to administration of purified C1INH.Copyright © 2010 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.