Extracellular nucleotides like ATP bind to cell surface receptors (P2 purinergic receptors) in many tissues. P2X receptor subtypes are intrinsic ion channels that mediate depolarization and influx of Ca 2+ , whereas the P2Y receptor subtypes couple through G proteins to activation of phospholipase Cฮฒ and mobilization of intracellular Ca 2+ . In nonskeletal tissues, extracellular ATP functions in neurotransmission, stimulation of secretion, regulation of cell proliferation, and induction of apoptosis. Multiple subtypes of P2 purinergic receptors are expressed in bone. P2Y purinergic receptors have been identified in osteoblasts and osteoclasts, and P2X purinergic receptors in osteoclasts. Bone cells exhibit a number of functional responses when exposed to extracellular nucleotides. These include enhancement of osteoblast responses to parathyroid hormone and stimulation of osteoclast formation and resorptive activity. Nucleotides accumulate at sites of inflammation and tissue injury, and therefore may serve as paracrine regulators of bone cell function in diseases such as rheumatoid arthritis and periodontitis. In addition, autocrine/paracrine signaling via release of nucleotides may underlie the physiological responses of skeletal tissues to mechanical stimuli. This article reviews work from our laboratories and others on the identity of purinergic receptor subtypes in osteoblasts and osteoclasts, their associated signal transduction mechanisms, and their roles in regulating bone cell function. We discuss the potential of P2 purinergic receptors as targets for the development of anabolic and antiresorptive drugs aimed at the treatment of osteoporosis and other bone disorders.