AbstractIt is now accepted that extracellular ATP and other nucleotides are potent signaling molecules, akin to neurotransmitters, hormones, and lipid mediators. In the liver, several clues support a significant role for extracellular ATP‐induced signaling pathways in the control of tissue homeostasis. First, ATP and other nucleotides are physiologically detected in extracellular fluids within the liver, including sinusoidal blood and intraductular bile, in various mammalian species including human and rodents. Moreover, finely tuned mechanisms of ATP release by different liver cell types have been described, under physiological cellular changes. In addition, most hepatic cells constitutively express, at the membrane level, several ATP‐metabolizing ectoenzymes and ATP‐sensitive receptors that modulate and transduce these mediator signals, respectively. Finally, hepatic cells also express numerous membrane transporters that actively contribute to purinergic salvage pathways. Once released in the extracellular medium, unmetabolized ATP molecules can bind to purinergic P2X and P2Y receptors, and subsequently trigger various intracellular signal transduction pathways collectively referred to as purinergic signaling. In the liver, purinergic signaling has been shown to regulate key basic cellular functions, such as glucose/lipid metabolism, protein synthesis and ionic secretion, and homeostatic processes, such as cell cycle, inflammatory response, and immunity. While the functional relevance of P2Y receptors in liver physiology has been well documented, limited information is available regarding the potential role of hepatic P2X receptors in the modulation of liver homeostasis.WIREs Membr Transp Signal2012,1:341–348. doi: 10.1002/wmts.32For further resources related to this article, please visit theWIREs website.