P2 membrane receptors are specifically activated by extracellular nucleotides like ATP, ADP, UTP, and UDP. P2 receptors are subdivided into metabotropic P2Y and ionotropic P2X receptors. They are expressed in all tissues and induce a variety of biological effects. In epithelia, they are found in both the basolateral and the luminal membranes. Their widespread luminal expression in nearly all transporting epithelia and their effect on transport are summarized. The P2Y₂ receptor is a prominent luminal receptor in many epithelia. Other luminal P2 receptors include the P2X₇, P2Y₄, and P2Y₆ receptors. Functionally, luminal P2Y₂ receptor activation elicits differential effects on ion transport. In nearly all secretory epithelia, intracellular Ca²⁺ concentration-activated ion conductances are stimulated by luminal nucleotides to induce Cl⁻, K⁺, or HCO secretion. This encompasses respiratory and various gastrointestinal epithelia or tissues like the conjunctiva of the eye and the epithelium of sweat glands. In the distal nephron, all active transport processes appear to be inhibited by luminal nucleotides. P2Y₂receptors inhibit Ca²⁺ and Na⁺ absorption and K⁺ secretion. Commonly, in all steroid-sensitive epithelia (lung, distal nephron, and distal colon), luminal ATP/UTP inhibits epithelial Na⁺ channel-meditated Na⁺absorption. ATP is readily released from epithelial cells onto their luminal aspect, where ecto-nucleotidases promote their metabolism. Adenosine generated by the action of 5′-nucleotidase may elicit further effects on ion transport, often opposite those of ATP. ATP release from epithelia continues to be poorly understood. Integrated functional concepts for luminal P2 receptors are suggested: 1) luminal P2 receptors are part of an epithelial “secretory” defense mechanism; 2) they may be involved in the regulation of cell volume when transcellular solute transport is out of balance;3) ATP and adenosine may be important autocrine/paracrine regulators mediating cellular protection and regeneration after ischemic cell damage; and 4) ATP and adenosine have been suggested to mediate renal cyst growth and enlargement in polycystic kidney disease.