Calcium-activated chloride channels (Cl_Ca) are ligand-gated anion channels as they have been shown to be activated by a rise in intracellular Ca²⁺ concentration in various cell types including cardiac, skeletal and vascular smooth muscle cells, endothelial and epithelial cells, as well as neurons. Because Cl_Ca channels are normally closed at resting, free intracellular Ca²⁺ concentration (~100 nmol/L) in most cell types, they have generally been considered excitatory in nature, providing a triggering mechanism during signal transduction for membrane excitability, osmotic balance, transepithelial chloride movements, or fluid secretion. Unfortunately, the genes responsible for encoding this class of ion channels is still unknown. This review centers primarily on recent findings on the properties of these channels in smooth muscle cells. The first section discusses the functional significance and biophysical and pharmacological properties of Cl_Ca channels in smooth muscle cells, and ends with a description of 2 candidate gene families (i.e., CLCA and Bestrophin) that are postulated to encode for these channels in various cell types. The second section provides a summary of recent findings demonstrating the regulation of native Cl_Ca channels in vascular smooth muscle cells by calmodulin-dependent protein kinase II and calcineurin and how their fine tuning by these enzymes may influence vascular tone. Key words: calcium-activated chloride channels, vascular smooth muscle cells, ion channels, calmodulin-dependent protein kinase II, calcineurin