Aims Dysregulation of bladder afferent activity and detrusor smooth muscle behavior leads to a constellation of lower urinary tract symptoms (LUTS), which includes overactive bladder (OAB). Current treatments for LUTS are poorly tolerated and may be associated with substantial adverse effects. Methods Major advances in the understanding of bladder neuroanatomy and the role of bladder afferent pathways in symptom generation suggest a range of targets for new therapeutic agents. Results A sensory role for urothelial and suburothelial structures has been established, as well as a cascade of afferent bladder signaling involving the bladder epithelium and detrusor muscle. Numerous inhibitory and stimulatory neurotransmitters and chemical mediators interact with a variety of specialized receptors and participate in signal transduction leading to wider neuroactivation. The blockade of muscarinic receptors, possibly mediated by muscarinic 2 (M2) receptors residing in the urothelium, has been shown to affect bladder afferent fibers, challenging the traditional concept that antimuscarinic therapy involves M3 receptor‐mediated effects on detrusor smooth muscle. The propagation of impulses to spinal and higher centers utilizes axonal fiber tracts remarkable for their morphologic and functional plasticity as bladder function becomes increasingly disordered. Conclusions These findings suggest that the etiology of LUTS includes enhanced, dysregulated, and perhaps maladaptive sensory signaling arising from numerous pelvic locales, including the most superficial epithelium of the bladder. Neurourol. Urodynam. 26:908–913, 2007. © 2007 Wiley‐Liss, Inc.