Angioedema involves submucosal/subcutaneous edema from increased vascular permeability, but the two major types have fundamentally different mechanisms requiring distinct treatments. Histamine-mediated (allergic) angioedema results from IgE-mediated mast cell degranulation releasing histamine, leukotrienes, and prostaglandins that increase vascular permeability. It almost always presents with concurrent urticaria (hives) and responds to epinephrine, antihistamines, and corticosteroids. ACE inhibitor-induced angioedema (ACEi-AE) has a completely different mechanism: ACE normally degrades bradykinin, a potent vasodilator and permeability factor. ACE inhibitors block this degradation, causing bradykinin accumulation. Bradykinin binds B2 receptors on endothelial cells, activating nitric oxide synthase and phospholipase A2, producing vasodilation and vascular leakage. ACEi-AE is bradykinin-mediated, NOT histamine-mediated — therefore antihistamines, epinephrine, and corticosteroids are INEFFECTIVE. ACEi-AE can occur at any point during ACE inhibitor therapy (25% of cases occur after >1 year of use), affects the lips, tongue, pharynx, and larynx preferentially, and is 3-5 times more common in African Americans due to genetic polymorphisms in aminopeptidase P and other bradykinin-degrading enzymes. Hereditary angioedema (HAE) is a third type caused by C1-inhibitor deficiency (types I and II) or gain-of-function Factor XII mutations (type...