It has long been recognized that interstitial cystitis (IC) is a disease of the urothelium. In this article, we review the results of published studies and present new data concerning the precise role of the bladder epithelium in IC. We discuss bladder defenses against both the penetration of urinary solutes and bacterial adherence, and we present new information about the proteoglycans that are present on the normal bladder. Previously published results and new data presented here support the conclusion that IC involves an aberrant differentiation program in the bladder urothelium that leads to altered synthesis of several proteoglycans, cell adhesion and tight junction proteins, and bacterial defense molecules such as GP51. These findings lend support to the rationale for glycosaminoglycan replacement therapy for the treatment of patients with IC.