This study investigated the role of P2Y purinergic receptor 12 (P2Y12) in osteoclast function. ADP-mediated stimulation of P2Y12 on osteoclasts enhanced adhesion and resorptive activity; these effects were not seen in P2y12−/− osteoclasts. P2y12−/− mice had decreased osteoclast resorptive activity and were partially protected from bone loss that occurred as a result of age, arthritis, osteoporosis or tumour growth. Moreover, wild-type mice treated with the clinical P2Y12 inhibitor clopidogrel were protected from bone loss, suggesting that P2Y12 inhibition is a potential target for this disorder.