Chronic urticaria (CU) is defined as wheals, angioedema, or both, that last more than 6 weeks. Second-generation antihistamines are considered the first-line therapy for CU. Unfortunately, many patients will fail antihistamines and require alternative therapy, including immune response modifiers or biologics. Multiple biological agents have been evaluated for use in antihistamine-refractory CU, including omalizumab, rituximab, and intravenous immunoglobulin; omalizumab is the most efficacious. Because of the success of omalizumab, multiple new biologics that are directed at the IgE pathway are under investigation. This review summarizes the relevant data regarding the efficacy of biologics in antihistamine-refractory CU.