Intracellular transduction pathways that are dependent on activation of the CaR by Ca_o²⁺ have been studied extensively in parathyroid and other cell types, and include cytosolic calcium, phospholipases C, A₂, and D, protein kinase C isoforms and the cAMP/protein kinase A system. In this study, using bone marrow cells isolated from CaR^-/- mice as well as DN-CaR-transfected RAW 264.7 cells, we provide evidence that expression of the CaR plays an important role in osteoclast differentiation. We also establish that activation of the CaR and resultant stimulation of PLC are involved in high Ca_o²⁺-induced apoptosis of mature rabbit osteoclasts. Similar to RANKL, Ca_o²⁺ (20 mM) appeared to trigger rapid and significant nuclear translocation of NF-B in a CaR- and PLC-dependent manner. In summary, our data suggest that stimulation of the CaR may play a pivotal role in the control of both osteoclast differentiation and apoptosis in the systems studied here through a signaling pathway involving activation of the CaR, phospholipase C, and NF-B.--Mentaverri, R., Yano, S., Chattopadhyay, N., Petit, L., Kifor, O., Kamel, S., Terwilliger, E. F., Brazier, M., Brown, E. M. The calcium sensing receptor is directly involved in both osteoclast differentiation and apoptosis.