Purinergic receptors are a family of ubiquitous transmembrane receptors comprised of 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 signaling 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 signaling through the Gq/PKC pathway and subsequent activation of Ca2+-dependent ion channels. P1 signaling is complex, with each of the four P1 receptors, A1, A2A, A2B, and A3, having a unique role in different epithelial tissue types. In colonic epithelium the A2B receptor plays a prominent role in regulating Cl- and water secretion. In airway epithelium, A2B and A1 receptors are implicated in the control of Cl- and other currents. In the renal tubular epithelium, A1, A2A, and A3 receptors have all been identified as playing a role in controlling the ionic composition of the lumenal fluid. Here we discuss the intracellular signaling pathways for each of these receptors in various epithelial tissues and their roles in pathophysiological conditions such as cystic fibrosis.