Chronic urticaria (CU) is a relatively common but vexing disease. The pathophysiology is based on the cutaneous mast cell release of mediators, predominantly histamine. Release can be induced via specific immunoglobulin E (IgE), components of complement activation and nonspecifically by various compounds including endogenous peptides, endorphins, and enkephalins. In >30% of CU patients, autoimmune phenomena have been found, characterized by positive autologous serum skin test, antibodies to the alpha-subunit of the basophil IgE receptor, to IgE itself, and, perhaps, the most clinically relevant, thyroid autoimmunity. Studies suggest that the products of the activated immune system can lower the cutaneous mast cell release threshold, possibly allowing activation by endogenous compounds. The resulting release of mediators produces the clinical picture of recurrent hives. Although the goal of management of CU is the identification of a treatable cause, in most CU patients, especially adults, a cause is not frequently found. Identified causes include drugs, foods, infections, immune complex production leading to urticarial vasculitis, autoantibody production, and underlying autoimmune disease, particularly autoimmune thyroiditis. The treatment of the thyroiditis with suppressive doses of thyroid hormone often results in the remission of the CU. Given the marginally effective and sometimes dangerous medical therapy available for CU, a systematic and thorough approach to identify a treatable cause in difficult CU patients is warranted.