The definition of interstitial cystitis (IC) has evolved over the years from being a well-defined entity characterized by diagnostic lesion (Hunner's ulcer) in the urothelium to a clinical diagnosis by exclusion (painful bladder syndrome (PBS). Although the etiology is unknown, a central theme has been an association with increased permeability of the bladder. This article reviews the evidence for increased permeability being important to the symptoms of IC/PBS and in treating the disorder. Recent work showing cross-communication among visceral organs is also reviewed to provide a basis for understanding IC/PBS as a systemic disorder of a complex, interconnected system consisting of the bladder, bowel and other organs, nerves, cytokine-responding cells and the nervous system.