Interstitial cystitis (IC) patients present with irritative and painful bladder symptoms and are diagnosed clinically by their symptoms, negative urine cultures, absence of other diseases, and cystoscopic findings of glomerulations and/or ulcers. The histological evaluation usually is described as nonspecific chronic inflammation. Although numerous theories of pathogenesis have been proposed, the etiology of IC is unknown. The hypothesized causes of IC include infectious, lymphovascular obstruction and neurogenic, endocrinologic, psychoneurotic, inflammatory (especially mast cells), and autoimmune pathologies. In this Review we discuss the evidence supporting a role for autoimmunity in IC and link the mast cell to the expression of the disease. Moreover, we discuss newly developed animal models that may provide insight into the etiology of IC.