From the earliest studies with epithelial cells implanted into detrusor muscle to later experiments on smooth muscle in defined collagen gels, cell niche and extracellular matrix (ECM) have been clearly shown to orchestrate cellular behavior and fate whether quiescent, migratory, or proliferative. Normal matrix can revert transformed cells to quiescence, and damaged matrix can trigger malignancy or dedifferentiation. ECM influence in disease, development, healing and regeneration has been demonstrated in many other fields of study, but a thorough examination of the roles of ECM in bladder cell activity has not yet been undertaken. Structural ECM proteins, in concert with adhesive proteins, provide crucial structural support to the bladder. Both structural and nonstructural components of the bladder have major effects on smooth muscle function, through effects on matrix rigidity and signaling through ECM receptors. While many ECM components and receptors identified in the bladder have specific known functions in the vascular smooth musculature, their function in the bladder is often less well defined. In cancer and obstructive disease, the ECM has a critical role in pathogenesis. The challenge in these settings will be to find therapies that prevent hyperproliferation and encourage proper differentiation, through an understanding of matrix effects on cell biology and susceptibility to therapeutics.