:  Osteoclasts are cells of monocyte–macrophage origin that degrade bone matrix. Receptor activator of NF‐κB ligand (RANKL) induces osteoclast formation in the presence of macrophage‐colony‐stimulating factor (M‐CSF) and costimulatory signals. RANKL induces activation of the TNF receptor‐associated factor 6 (TRAF6) and c‐Fos pathways, which lead to the osteoclast‐specific event, that is, autoamplification of nuclear factor of activated T cells (NFAT)c1, the master transcription factor for osteoclast differentiation. Autoamplification of NFATc1 is dependent on the calcium signaling of immunoglobulin‐like receptors associated with immunoreceptor tyrosine‐based activation motif (ITAM)‐harboring adaptors. In addition to the calcineurin–NFATc1 axis, calcium signaling activates the calmodulin‐dependent kinase pathway, which also plays a critical role in osteoclast formation. Such advances in the understanding of the molecular mechanism of osteoclast differentiation are expected to lead to novel therapeutic approaches to bone diseases.