After the identification of the cystic fibrosis transmembrane conductance regulator (CFTR) gene, numerous expression studies verified that CFTR is a cAMP-dependent chloride channel (1–3). Given that chloride impermeability is the signature of CF-affected epithelium, these data were completely consistent with previously described findings. However, a number of other characteristics of CF-affected epithelia such as abnormal sodium transport could not explained by CFTR’s chloride channel activity. In an attempt to reconcile this apparent discrepancy, further electrophysiologic studies were performed and demonstrated that CFTR has a variety of secondary functions including that of channel regulator (4). CFTR has been shown to regulate and/or modulate the epithelial sodium channel (4,7), and the outwardly rectifying chloride channel (4,8–10). The mechanism(s), by which CFTR can interact or affect these other channels is unknown. While trying to identify the exact mechanism(s) investigators have examined whether CFTR could affect ATP transport to the extracellular surface (11,12). Alterations in extracellular ATP could explain many of the secondary abnormalities observed in CF-affected epithelia. For instance, extracellular ATP has been shown to have a variety of effects on airway epithelial cells, including altering ciliary beat, and stimulating submucosal gland secretion (13). Furthermore, in experimental models it has been shown to activate of a variety of “non-CFTR” chloride channels (13-16) and regulate the epithelial sodium transport (13). It has been postulated that CFTR (1) could affect ATP transport by acting as a transporter or pump for ATP, (2) could conduct ATP directly or could be associated with an ATP channel or pore, (3) or could affect the release of vesicles that contain ATP (17) (Fig. 1).