Current evidence from clinical and laboratory studies confirms that mast cells play a central role in the pathogenesis and pathophysiology of interstitial cystitis (IC). In this article, we focus on the role of the mast cell in IC and examine the ways in which mast cells and other pathophysiologic mechanisms are interrelated in this disease. Identifying the patients with IC who have mast cell proliferation and activation will enable us to address this aspect of disease pathophysiology in these individuals with targeted pharmacotherapy to inhibit mast cell activation and mediator release.