Two families of proteins, the bestrophins (Best) and the recently cloned TMEM16 proteins (anoctamin, Ano), recapitulate properties of Ca 2+ -activated Cl - currents. Best1 is strongly expressed in the retinal pigment epithelium and could have a function as a Ca 2+ -activated Cl - channel as well as a regulator of Ca 2+ signaling. It is also present at much lower levels in other cell types including epithelial cells, where it regulates plasma membrane localized Cl - channels by controlling intracellular Ca 2+ levels. Best1 interacts with important Ca 2+ -signaling proteins such as STIM1 and can interact directly with other Ca 2+ -activated Cl - channels such as TMEM16A. Best1 is detected in the endoplasmic reticulum (ER) where it shapes the dynamic ER structure and regulates cell proliferation, which could be important for renal cystogenesis. Ca 2+ -activated Cl - channels of the anoctamin family (TMEM16A) show biophysical and pharmacological properties that are typical for endogenous Ca 2+ -dependent Cl - channels. TMEM16 proteins are abundantly expressed and many reports demonstrate their physiological importance in epithelial as well as non-epithelial cells. These channels are also activated by cell swelling and can therefore control cell volume, proliferation and apoptosis. To fully understand the function and regulation of Ca 2+ -activated Cl - currents, it is necessary to appreciate that Best1 and TMEM16A are embedded in a protein network and that they probably operate in functional microdomains.