Chronic urticaria (CU) is a common and long-lasting mast cell-mediated skin disease associated with psychiatric and autoimmune comorbidities, high economic costs, and considerable impact on quality of life. Available therapies show limited efficacy in many CU patients, which may be related to distinct underlying pathophysiology. Targeted and disease-modifying treatments with higher and broader efficacy are needed and are under development for CU. These novel drugs, small molecules, and monoclonal antibodies target mast cells and their receptors, signaling pathways, or mediators and other immune cells. In this article, the authors focus on the most promising emerging therapeutics in advanced development and discuss their potential place in future management of CU.