TMEM16A (also known as anoctamin-1), a plasma membrane protein with eight putative transmembrane segments, has been recently identified as an important component of calcium-activated chloride channels, CaCCs (1-3). Indeed, expression of TMEM16A by transient or stable transfection causes the appearance of calcium- and voltage-dependent chloride currents. The function of TMEM16A appears to be regulated by alternative splicing and the use of alternative promoters. These processes generate various protein isoforms. At least three exons, ex6b, ex13, and ex15, are differently included/skipped in various organs. Such exons code for segments called (b), (c), and (d), respectively, localized in the intracellular regions of TMEM16A protein. A fourth segment, termed (a), and coding for the first 116 amino acid residues at the amino-terminus, may be skipped when an alternative promoter is used. Analysis of TMEM16A splicing in various adult human organs indicates that the most abundant isoforms are (abc) and (ac). The former one, having the inclusion of the 22 amino acid-long segment b (ex6b), localized in the amino terminus, close to the first transmembrane domain, shows a calcium sensitivity lower than that of (ac) isoform. The role of segment b is at present unclear but it may be proposed that it has an inhibitory function that is relieved by increasing cytosolic calcium concentration. Interestingly, the skipping of all alternative segments generates a shorter version of the protein, called TMEM16A(0), which is completely devoid of voltage-dependence. Analysis of TMEM16A primary sequence has not revealed canonical sequences for calcium or calmodulin binding. However, mutagenesis of specific amino acid residues appears to shift the apparent affinity for calcium. CaCCs represent a potential drug target for the treatment of various human diseases (4,5). Stimulation of CaCCs in the airways may be a strategy to improve mucociliary clearance in cystic fibrosis and other chronic respiratory diseases. On the other hand, pharmacological modulation of CaCCs in smooth muscle cells may be beneficial for hypertension, asthma or gastrointestinal motility disorders. Finally, it has been reported that TMEM16A is overexpressed in different types of human cancers (5). This finding may indicate TMEM16A/CaCCs as possible targets for anti-cancer therapies and/or as biomarkers for diagnostic and prognostic purposes.