AbstractCellular release of nucleotides is of physiological importance to regulate and maintain cell function and integrity. Also in the tubular and collecting duct system of the kidney, nucleotides are released in response to changes in cell volume or luminal flow rate and act in a paracrine and autocrine way on basolateral and luminal P2Y receptors. Recent studies using gene knockout mice assigned a prominent role to G protein‐coupled P2Y2receptors, which are activated by both ATP and UTP. The antidiuretic hormone, arginine‐vasopressin (AVP), and possibly an increase in collecting duct cell volume induce ATP release. The subsequent activation of P2Y2receptors inhibits AVP‐induced cAMP formation and water reabsorption, which stabilizes cell volume and facilitates water excretion. An increase in NaCl intake enhances luminal release of ATP and UTP in the aldosterone‐sensitive distal nephron which by activating apical P2Y2receptors and phospholipase C lowers the open probability of the epithelial sodium channel ENaC, thereby facilitating sodium excretion. Thus, the renal ATP/UTP/P2Y2receptor system not only serves to preserve cell volume and integrity but is also regulated by stimuli that derive from body NaCl homeostasis. The system also inhibits ENaC activity during aldosterone escape, i.e., when sodium reabsorption via ENaC is inappropriately high. The P2Y2receptor tone inhibits the expression and activity of the Na–K–2Cl cotransporter NKCC2 in the thick ascending limb and mediates vasodilation. While the role of other P2Y receptors in the kidney is less clear, the ATP/UTP/P2Y2receptor system regulates NaCl and water homeostasis and blood pressure.WIREs Membr Transp Signal2012, 1:731–742. doi: 10.1002/wmts.61For further resources related to this article, please visit theWIREs website.