NF-kappaB is a vital component of the molecular programs for immune cell development and activation, inflammatory responses, and osteoclast differentiation. This transcriptional regulatory family is activated by diverse immunological and inflammatory stimuli and contributes to both positive feedback of the immune and osteolytic responses as well as their resolution. The ubiquilous expression of NF-kappaB components in osteoclasts and other immune cells creates an opportunity to gain a better understanding of the complex interplay between the immune and skeletal systems in physiological and pathological conditions and also makes NF-kappaB an important target in the treatment of autoimmune, inflammatory, and osteolytic diseases. Indeed, many genetic murine models have recently been developed which highlight the importance of NF-kappaB in basic processes including lymphocyte development, macrophage activation, and osteoclast differentiation. Furthermore, inhibition of NF-kappaB signaling has been demonstrated to ameliorate tissue inflammation and osteolysis in mouse models of inflammatory disease. A more complete understanding of the immunological factors that regulate NF-kappaB and the role that NF-kappaB plays in the immune and skeletal systems will elucidate potential avenues for intervening therapeutically in the pathological conditions of inflammation and osteolysis.