Summary:  Bone metabolism is regulated by hormonal or local factors in the bone microenvironment, and recent studies have revealed that bone homeostasis is also influenced by immune system. The term ‘osteoimmunology’ has been proposed to explain the cross-talk between bone and the immune system. A critical element in this cross-talk is the inducible transcription factor nuclear factor-κB (NF-κB), which regulates gene expression during inflammatory and immune responses. However, NF-κB-signaling pathways are also important for bone homeostasis, in particular for osteoclast differentiation. By bridging inflammation and bone homeostasis, NF-κB also contributes to the onset and progression of arthritis. Several natural compounds, synthetic drugs, and gene-transfer technologies that lead to inhibition of the inhibitor of NF-κB kinase (IKK)/NF-κB activation pathway can prevent arthritis in animal models. In this review, we discuss the signaling pathway that leads to NF-κB activation and the role of NF-κB on osteoclast differentiation. Furthermore, we discuss the possibility that inhibition of NF-κB might provide novel therapeutic approach for inhibiting bone destruction in rheumatoid arthritis.