Osteoclasts are cells of the hematopoietic lineage that are responsible for bone resorption. Their activity is crucial in the initiation of bone remodeling and for maintenance of a strong and healthy skeleton. However, in a number of diseases, including inflammatory disorders, inappropriately high osteoclast activity results in excessive bone degradation, bone loss, and subsequently fractures. A range of P2X purinergic receptors are expressed in bone cells, and osteoclasts express most of the P2X receptors. However, until recently only the role of the P2X7 receptor subtype in normal and pathophysiologic bone metabolism was documented while very few studies addressed the role of the remaining six P2X receptor subtypes. Recently, studies have documented that the P2X5 receptor not only controls osteoclastic bone resorption but also mediates inflammation-induced bone loss, while P2X2/3 receptors have dual functions in bone, both regulating bone resorption and mediating bone pain. Finally, an in vivo study showed that reduced P2X7 receptor function aggravates estrogen-withdrawal-induced bone loss, which is in line with the growing number of reports cementing the association between P2X7 receptor polymorphisms and development of osteoporosis and fracture risk. The studies reviewed in this article provide intriguing results highlighting the potential of P2X receptors as promising pharmaceutical targets in the treatment of bone loss associated with inflammatory (and other) diseases.