Intracellular ATP, the energy source for many reactions, is crucial for the activity of plasma membrane pumps and, thus, for the maintenance of transmembrane ion gradients. Nevertheless, ATP and other nucleotides/nucleosides are also extracellular molecules that regulate diverse cellular functions, including ion transport. In this review, I will first introduce the main components of the extracellular ATP signalling, which have become known as the purinergic signalling system. With more than 50 components or processes, just at cell membranes, it ranks as one of the most versatile signalling systems. This multitude of system components may enable differentiated regulation of diverse epithelial functions. As epithelia probably face the widest variety of potential ATP‐releasing stimuli, a special attention will be given to stimuli and mechanisms of ATP release with a focus on exocytosis. Subsequently, I will consider membrane transport of major ions (Cl⁻, HCO₃⁻, K⁺ and Na⁺) and integrate possible regulatory functions of P2Y2, P2Y4, P2Y6, P2Y11, P2X4, P2X7 and adenosine receptors in some selected epithelia at the cellular level. Some purinergic receptors have noteworthy roles. For example, many studies to date indicate that the P2Y2 receptor is one common denominator in regulating ion channels on both the luminal and basolateral membranes of both secretory and absorptive epithelia. In exocrine glands though, P2X4 and P2X7 receptors act as cation channels and, possibly, as co‐regulators of secretion. On an organ level, both receptor types can exert physiological functions and together with other partners in the purinergic signalling, integrated models for epithelial secretion and absorption are emerging.