Chronic urticaria is a common skin disease without a clear etiology in the vast majority of cases. The similarity of symptoms and lesion pathology to allergen-induced skin reactions supports the idea that skin mast cell and blood basophil IgE receptor activation is involved; however, no exogenous allergen trigger has been identified. The presence of serum IgG autoantibodies targeting IgE or the IgE receptor in ∼40% of CIU cases supports the theory of an autoimmune basis for the disease. However, issues remain with the assays to detect autoantibodies among other serum factors, the relationship of autoantibodies to CIU disease activity, and the occurrence of autoantibodies in healthy subjects. Other studies have identified altered IgE receptor degranulation that reverts in disease remission and is accompanied by changes in signaling molecule expression and function in mast cells and basophils in active CIU subjects. The arrival of therapies targeting IgE and the IgE receptor pathway elements has potential use in CIU.