The urothelium plays a pivotal role as a barrier between urine and its solutes and the underlying bladder. Bladder surface mucus is a critical component of this function. The biologic activity of mucus that imparts this barrier function is generated by the highly anionic polysaccharide components (eg, glycosaminoglycans), which are extremely hydrophilic and trap water at the outer layer of the umbrella cell. This trapped water forms a barrier at the critical interface between urine and the bladder. The result is a highly impermeable urothelium that serves as a key protective barrier for the bladder interstitium. In interstitial cystitis (IC), disruption of the urothelial barrier may initiate a cascade of events in the bladder, leading to symptoms and disease. Specifically, epithelial dysfunction leads to the migration of urinary solutes, in particular, potassium, that depolarize nerves and muscles and cause tissue injury. Exogenous heparinoids can restore the barrier function of the urothelium and thus successfully treat patients with IC. Groups of patients who have been given a diagnosis of IC, chronic prostatitis, and urethritis have been shown to have IC by virtue of their shared potassium sensitivity. It would seem, therefore, that mucous deficiency may be present throughout the lower urinary tract. If one is to rename these diseases, perhaps it is best to do so in reference to a shared loss of epithelial barrier function. A name such as lower urinary dysfunctional epithelium would incorporate all of these diseases under a single pathophysiologic process. As a result of these discoveries, a new paradigm for diagnosis and treatment is emerging.