Osteoclasts are responsible for bone resorption and play a pivotal role in the pathogenesis of osteolytic disorders. NF-κB is a set of nuclear factors that bind to consensus DNA sequences called κB sites, and is essential for osteoclast formation and survival. NF-κB signalling pathways are strictly regulated to maintain bone homeostasis by cytokines such as RANKL, TNF-α and IL-1, which differentially regulate classical and/or alternative NF-κB pathways in osteoclastic cells. These pathways are also modulated by NF-κB mediators, including TRAF6, aPKC, p62/SQSTM1 and deubiquitinating enzyme CYLD that are involved in the ubiquitin–proteasome system during RANK-mediated osteoclastogenesis. Abnormal activation of NF-κB signalling in osteoclasts has been associated with excessive osteoclastic activity, and frequently observed in osteolytic conditions, including periprosthetic osteolysis, arthritis, Paget's disease of bone, and periodontitis. NF-κB modulators such as parthenolide and NEMO-binding domain peptide demonstrate therapeutic effects on inflammation-induced bone destruction in mouse models. Unravelling the structure and function of NF-κB pathways in osteoclasts and other cell types will be important in developing new strategies for treatments of bone diseases.