Calcium-activated chloride channels (CaCCs) participate in many different physiologic processes such as transepithelial transport, excitability of neurons and muscle cells, and oocyte fertilization. Within the airways, they contribute to epithelial fluid secretion. This review focuses on three outstanding questions about CaCCs. First, although their biophysical fingerprint (anion selectivity, Ca2+ and voltage dependence, kinetics) is fairly well established, the molecular identity of CaCCs is still unresolved. CLCA, a family of proteins of which four members have so far been identified in humans, has been proposed to mediate calcium-activated chloride currents. However, the biophysical profile and expression pattern of endogenous CaCCs differ from those of the CLCA proteins. Another family of membrane proteins, the bestrophins, has recently been shown in transfected HEK293 cells to confer anion-selective currents that are activated by submicromolar Ca2+ concentrations. Second, pharmacologic tools to manipulate CaCCs are poorly selective. This lack of specificity not only hampers the structural and functional characterization of these channels but also restricts therapeutic options for altering CaCC function. Finally, potential pitfalls with respect to CaCCs as molecular targets for cystic fibrosis therapy are discussed.