Purinergic receptors are a family of ubiquitous transmembrane receptors comprising two classes, P1 and P2 receptors, which are activated by adenosine and extracellular nucleotides (i.e. ATP, ADP, UTP and UDP), respectively. These receptors play a significant role in regulating ion transport in epithelial tissues through a variety of intracellular signalling pathways. Activation of these receptors is partially dependent on ATP (or UTP) release from cells and its subsequent metabolism, and this release can be triggered by a number of stimuli, often in the setting of cellular damage. The function of P2Y receptor stimulation is primarily via signalling through the G(q)/PLC-beta pathway and subsequent activation of Ca(2+)-dependent ion channels. P1 signalling is complex, with each of the four P1 receptors A(1), A(2A), A(2B), and A(3) having a unique role in different epithelial tissue types. In colonic epithelium the A(2B) receptor plays a prominent role in regulating Cl(-) and water secretion. In airway epithelium, A(2B) and A(1) receptors are implicated in the control of Cl(-) and other currents. In the renal tubular epithelium, A(1), A(2A), and A(3) receptors have all been identified as playing a role in controlling the ionic composition of the lumenal fluid. Here we discuss the intracellular signalling pathways for each of these receptors in various epithelial tissues and their roles in pathophysiological conditions such as cystic fibrosis.