Context: Interstitial cystitis is a multifactorial chronic and debilitating disease which is commonly associated with pain localized in the bladder region, increased urinary frequency, urgency and nocturia. Due to the high prevalence of pain in the population affected more recently the condition is often referred to as interstitial cystitis / bladder pain syndrome (IC/BPS). Evidence Acquisition: Although IC presents with many different symptoms, researchers have formulated three different theories, which are not mutually exclusive, to explain IC pathology: the first is related to the alteration of the proteoglycan and protein junction composition, structure and presence in the urothelium. The second is an immune induced IC resulting from an increased number of activated mast cells in the bladder internal layers, such as detrusor muscle (DM), and mucosa/submucosa. The third type, which is closely related to the second one, is due to a sensory nerve sensitization as an effect of neurotrophic factors molecule release. Results: Previous classification has been mirrored in the development of various in vitro and in vivo disease models created to mimic IC, as well as in the available therapies used to treat the condition to date. Conclusions: This review will summarize the most recent advances in the field, related to the different causative factors contributing to the development of the condition, the in vivo models used as well as the evidence they provide in advancing our knowledge and their limitations. The focus will be on works reporting on IC in the domain related to alterations in proteoglycans and cellular junction, specifically their composition, structure and appearance in the urothelium, and also discuss present and future therapies. Conclusions: This review will summarize the most recent advances in the field, related to the different causative factors contributing to the development of the condition, the in vivo models used as well as the evidence they provide in advancing our knowledge and their limitations. The focus will be on works reporting on IC in the domain related to alterations in proteoglycans and cellular junction, specifically their composition, structure and appearance in the urothelium, and also discuss present and future therapies.