Epithelial cells exhibit regulated release of ATP. Once outside of the cell, ATP in nanomolar concentrations functions as an autocrine/paracrine signal modulating a broad range of cell and organ functions through activation of purinergic receptors in the plasma membrane. The mechanisms responsible for ATP release have not been defined. In liver cells, there is evidence for ATP translocation through a conductive, channel-mediated pathway. In addition, indirect observations support a second potential mechanism involving exocytosis of ATP-enriched vesicles. Notably, stimuli that increase ATP release are associated with a five- to ten-fold increase in the rate of exocytosis; and inhibition of the exocytic response impairs cellular ATP release. More recent evidence suggests that these vesicles can be visualized, supporting the concept that in liver cells, ATP release is mediated in part by exocytosis of a pool of vesicles enriched in ATP, which can be mobilized within seconds in response to changing physiologic demands.