Purpose: The etiology of bladder pain syndrome/interstitial cystitis is poorly understood. The possibility that epigenetic reprogramming may have a role is discussed. Materials and Methods: A literature search was performed with the Entrez-PubMed® database using the key words urinary bladder, epigenetics, epigenetic mechanisms, interstitial cystitis, diagnosis, etiology, urothelial cells, mast cells, nerve fibers, nerves, nerve growth factor, recurrent injury, stem cells, inflammatory mediators and demethylases. Results: The uroepithelium is intimately associated with the nervous system. Sensory input at the apical surface of umbrella cells regulates bladder function via a transmural signaling pathway. When umbrella cells are shed in response to noxious stimuli, stem cells in the basal layer become exposed. The polycomb group genes are key in the maintenance of adult stem cells. The polycomb group genes mediate gene silencing and repress transdifferentiation by methylating lysine 27 of histone H3 (H3K27me3). Jmjd3, an enzyme demethylating H3K27me3, antagonizes polycomb group genes mediated silencing. Inflammatory stimuli are strong inducers of Jmjd3 and may reverse gene silencing in stem cells, modifying the differentiation pattern. Epigenetic processes involving H3K27 methylation are multistable processes. Transient signaling, eg by lipopolysaccharide, triggers epigenetic reprogramming and establishes one of the alternative regulatory states. Once established such states can be maintained and propagated even in the absence of the initial signal. Conclusions: We postulate that similar epigenetic reprogramming mechanisms in the bladder may provide an explanation for uroepithelial, mast cells and nerve cell abnormalities in bladder pain syndrome/interstitial cystitis, as well as propagation of this altered state in the absence of the signal that may have triggered it. It also provides a new experimental paradigm for exploring the etiology of bladder pain syndrome/interstitial cystitis. Data supporting this hypothesis would provide a rationale for new diagnostic as well as treatment options for bladder pain syndrome/interstitial cystitis. © 2009 American Urological Association.