Epithelial cells express many types of anion conductance. Although both CFTR and the CICs have been discussed briefly above, other anion channels that are not yet identified at the molecular level include those that are responsible for volume regulation. In addition, several intracellular anion channels have been identified that may be trafficked to the plasma membrane under certain conditions. Similarly, the mechanisms underlying Ca2+-mediated Cl-secretion have proved difficult to pin down. This is due in part to the pluripotent nature of the message, and also to the number of potential targets. The difficulty of distinguishing between direct effects of Ca2+on epithelial conductance and those due to differences in driving force was alluded to above. However, this secretory pathway is of considerable significance, not least because it provides an alternative strategy for increasing epithelial Cl-secretion in CF. Despite the identification of CIC-3 as a potential CaCC, the CLCAs provide the best overall candidates for the role of CaCC that have been cloned to date. Even so, it is unlikely that the CLCAs account for all the different phenotypes of CaCCs that have been identified. Determining whether the CLCAs truly represent an epithelial CaCC or a component thereof will be a formidable challenge. © 2002.