Ca²⁺‐activated chloride channels (CaCCs) regulate numerous physiological processes including epithelial transport, smooth muscle contraction and sensory processing. Anoctamin‐1 (ANO1, TMEM16A) is a principal CaCC subunit in many cell types, yet our understanding of the mechanisms of ANO1 activation and regulation are only beginning to emerge. Ca²⁺ sensitivity of ANO1 is rather low and at negative membrane potentials the channel requires several micromoles of intracellular Ca²⁺ for activation. However, global Ca²⁺ levels in cells rarely reach such levels and, therefore, there must be mechanisms that focus intracellular Ca²⁺ transients towards the ANO1 channels. Recent findings indeed indicate that ANO1 channels often co‐localize with sources of intracellular Ca²⁺ signals. Interestingly, it appears that in many cell types ANO1 is particularly tightly coupled to the Ca²⁺ release sites of the intracellular Ca²⁺ stores. Such preferential coupling may represent a general mechanism of ANO1 activation in native tissues.