In the past, a number of candidates have been proposed to form Ca2+ activated Cl- currents, but it is only recently that two families of proteins, the bestrophins and the TMEM16-proteins, recapitulate reliably the properties of Ca2+ activated Cl- currents. Bestrophin 1 may form Ca2+ activated chloride channels and, at the same time, affect intracellular Ca2+ signaling. In epithelial cells, bestrophin 1 probably controls receptor mediated Ca2+ signaling. It may do so by facilitating Ca2+ release from the endoplasmic reticulum, thereby indirectly activating membrane localized Ca2+ dependent Cl- channels. In contrast to bestrophin 1, the Ca2+ activated Cl- channel TMEM16A (anoctamin 1, ANO1) shows most of the biophysical and pharmacological properties that have been attributed to Ca2+ dependent Cl- channels in various tissues. TMEM16A is broadly expressed in both mouse and human tissues and is of particular importance in epithelial cells. Thus exocrine gland secretion as well as electrolyte transport by both respiratory and intestinal epithelia requires TMEM16A. Because of its role for Ca2+ dependent Cl- secretion in human airways, it is likely to become a prime target for the therapy of cystic fibrosis lung disease, caused by defective cAMP-dependent Cl- secretion. When we analyzed expression of all ten members (ANO1- ANO10) in a broad range of murine tissues, we detected predominant expression of ANO1, 6, 7, 8, 9, 10 in epithelial tissues, while ANO2, 3, 4, 5 are common in neuronal and muscle tissues. When expressed in Fisher Rat Thyroid (FTR) cells, most ANO proteins localized to the plasma membrane but only ANO1, 2, 6 and 7 produced Ca2+ activated Cl- conductance. Patch clamping indicated that anoctamins produced chloride currents, albeit with very different Ca2+ sensitivity and activation time. We propose that different tissues express a particular set of anoctamins. In conjunction with a number of splice variants, which probably exists for each TMEM16-paralog, a cell and tissue specific Ca2+ dependent Cl- conductance will be formed.