The pathophysiology of chronic urticaria is complex, influenced by various mediatory pathways and cytokine networks, which are derived from and interactive with a myriad of inflammatory cells. A knowledge of these pathophysiologic mechanisms is important toward an understanding of chronic urticaria and to promote rational designs for the development of novel therapies of chronic urticarial syndromes. Topics discussed in this article include mast cell biology, autoimmunity, mast cell interaction with cutaneous sensory nerves, and the inflammatory process.