The unique physiological properties of the diverse array of cells within the bladder wall enable its normal functions of filling and emptying. Studies of diseased bladders by our group and others have shown that lesions tend to occur in multiple cell types (urothelium, nerves, interstitial cells (IC) or smooth muscle) underpinning dysfunction. The spinal cord injured (SCI) rat bladder exhibits early areflexia followed by chronic overactivity and late decompensation. Loss of the urothelium in the first few days after SCI is reversed by week 2 (1) and our recent (unpublished) work has shown that this is accompanied by acute damage to the interstitial cells of the lamina propria (IC-LP). Restoration of the IC-LP occurs by day 7 during urothelial regeneration. Patchy denervation after SCI is associated with loss of a population of detrusor IC indicating that the survival of some IC is dependent on normal nerve interactions (2). In acute, areflexic SCI, many of the IC proliferate and undergo phenotype change through myofibroblastic to de novo smooth muscle formation, both in the detrusor and in the lamina propria. This at least partly accounts for characteristic SCI bladder smooth muscle hypertrophy which is a pathophysiological response to urinary retention.Other insults to bladder function include diabetes and pelvic radiation therapy, both of which cause changes to the physiology of urothelial cells, IC and smooth muscle. The available experimental evidence will be presented with emphasis on disruption of cell-cell signaling with key areas of current and future research highlighted.