ATP serves not only as an energy source for all cell types but as an extracellular messenger for autocrine and paracrine signaling involving in a versatile role in modulating various cellular functions. This review summarizes the efflux pathways of ATP released from airway epithelial cells, the signal pathways through which ATP induces ion transport by the epithelia of airway, as well as its epithelium-dependent modulation of smooth muscle contraction of airway and the mechanism underlying in airway diseases.