The wall of the urinary bladder comprises a complex cellular structure whose complement of specific cell types and physiological cellular interactions have been shown in recent years to be more extensive than previously understood. Classically, the urothelium was considered as a passive barrier providing an important separation of urine and bladder smooth muscle and nerves. Yet, the urothelial cells are now known to participate in bladder function by sensing and responding to changes in the environment such as pH, temperature and stretch by releasing signalling molecules including acetylcholine and ATP (1). Much attention has been given to the role of afferent nerves and how they interact with urothelial cells, intersitial cells and smooth muscle (2). In the last decade, much work on the novel interstitial cells which occupy the sub-urothelial lamina propria layer (IC-LP) and the detrusor layer (intramuscular IC-IM and interbundle IC-IB) has provided new avenues of research into normal and dysfunctional bladder physiology (3). The dual functions of bladder filling and emptying require coordination between the activities of smooth muscle, nerves, interstitial cells and the urothelium. During filling, relaxation of detrusor smooth muscle is important to enable urine storage at low intravesical pressures. Yet, low-level spontaneous, myogenic activity occurs during filling in detrusor smooth muscle which is considered to maintain the bladder wall in the optimal shape for efficient emptying. This activity appears to occur in discrete areas of the bladder wall which remain uncoordinated during filling. When a conscious decision has been made to void, the smooth muscle must then contract in a highly coordinated fashion and this is under parasympathetic neuronal control. Recent insights on the role of the mucosal layer on spontaneous activity will be presented with particular reference to interstitial cells. It has been shown that the urothelium provides inhibitory signalling to detrusor smooth muscle through urothelium derived inhibitory factor (4). Conversely others have shown that the urothelium and potentially other sub-urothelial components enhance detrusor contractility (5). Work from our laboratory on animal models of neurogenic dysfunctional bladder including spinal cord injured (SCI, 6) and denervated bladders indicates different physiological roles for IC-LP and detrusor IC. In chronic SCI, loss of IC-LP and detrusor IC was associated with a hypercompliant phenotype and long-duration spontaneous contractions. In denervated bladders, maintenance of IC-LP but loss of detrusor IC was associated with high frequency, increased amplitude spontaneous contractions, indicative of an overactive phenotype. These observations suggest that (a) IC-LP may have a pacemaker-type function, modulating or driving smooth muscle spontaneous activity and (b) detrusor IC may have an inhibitory function, limiting spontaneous contractions of the detrusor during filling. Physiological evidence in support of these hypotheses include the findings that IC-LP exhibit spontaneous depolarizing calcium activated chloride currents (7), not found in detrusor IC which display hyperpolarizaing spontaneous transient outward BK currents (RMJ Cunningham and KD McCloskey, unpublished observations). The current state of knowledge in bladder basic research will be discussed with significant gaps in our knowledge highlighted and key areas of future research suggested.