AbstractOsteoclasts are large, multinucleated cells responsible for the resorption of bone and other mineralized tissues. Whereas low concentrations of extracellular ATP stimulate osteoclast formation and resorptive activity, high concentrations inhibit osteoclast formation. Cell surface receptors for nucleotides are classified into two families—P2X (ligand‐gated channels nonselective for cations) and P2Y (G‐protein‐coupled receptors linked, in most cases, to release of Ca2+ from intracellular stores). Several subtypes of P2 receptors are expressed by mammalian osteoclasts. The P2X4 receptor has been identified at both protein and messenger RNA levels and ATP activates a nonselective cation current with properties similar to that mediated by the cloned P2X4 channel. The P2X2 receptor is also expressed; however, currents with properties of P2X2 have yet to be identified. Functional and expression studies also support the existence of the P2X7 receptor, which is activated by high concentrations of ATP. Application of nucleotides to osteoclasts elicits transient elevation of cytosolic free Ca2+ concentration and activation of Ca2+‐dependent K+ channels. Both these responses are mediated, at least in part, by release of Ca2+ from intracellular stores, consistent with the presence of functional P2Y receptors. Expression of P2Y1 and P2Y2 receptors has been demonstrated in mammalian osteoclasts. The presence of multiple subtypes of P2 receptors may account for the biphasic effects of extracellular nucleotides on osteoclast function. These receptors represent potential targets for the development of novel therapeutics to inhibit bone resorption in diseases such as rheumatoid arthritis, osteoporosis, tumor‐induced osteolysis, and periodontitis. Drug Dev. Res. 53:130–139, 2001. © 2001 Wiley‐Liss, Inc.