Rapid progress has been made in the determination of specific ion channels expressed in airway smooth muscle cells and their role in excitation–contraction coupling. The combination of molecular biology and molecular physiology has provided insight into the properties of voltage-dependent cation (calcium and potassium) channels and their regulation by excitatory and inhibitory signaling processes. In this brief review, we will focus on calcium release and calcium-activated chloride channels. The former channels mediate receptor-activated calcium release, and the latter channels are opened following this release event. Moreover, the discovery of spontaneous calcium release events, or “calcium sparks,” in smooth muscle, suggests an unanticipated level of regulation. Intracellular calcium release can drive electrical activity by the activation of calcium-dependent sarcolemmal ion channels, including calcium-activated chloride channels. These channels activate briefly but undergo a rapid phosphorylation by calcium/calmodulin-dependent protein kinase, which uncouples channel activity from cytosolic calcium. The coupling between intracellular calcium release and depolarizing chloride currents represents a potentially important signaling system in airway smooth muscle. Kotlikoff MI, Wang Y-X. Calcium release and calcium-activated chloride channels in airway smooth muscle cells.