Nuclear factor-kappa B (NF-kappaB) is a set of five polypeptide transcription factors, called p50, p52, p65 (also called Rel A), Rel B, and c-Rel, which regulate the expression of a variety of genes involved in immune and inflammatory responses. They were originally named because they were considered essential regulators of B cell kappa light chain expression. More recent studies indicate that NF-kappaB proteins are involved in the regulation of a variety of other cell functions, including cell proliferation, responses to stress, and apoptosis. NF-kappaB heterodimers reside in the cytoplasm of cells bound to inhibitory proteins, the two commonest of which are IkappaBalpha and IkappaBbeta, which prevent NF-kappaB from entering the nucleus. When cells are stimulated, IkappaB is phosphorylated by specific IkappaB kinases and subsequently is ubiquitinated and degraded in proteosomes. This allows NF-kappaB to translocate to the nucleus to regulate the expression of a growing list of genes, including the proinflammatory cytokines, interleukin-1 (IL-1), IL-6, and tumor necrosis factor. IL-1 and tumor necrosis factor in turn also regulate the expression of NF-kappaB. Thus, once activated, NF-kappaB may be involved in upregulatory loops, which can amplify the effects of the initiating stimulus. Because these proinflammatory cytokines have been implicated in the pathogenesis of estrogen deficiency and inflammation-related bone loss, it is likely that NF-kappaB has a significant role in the increased generation and function of osteoclasts in these circumstances. However, an unexpected and essential role of NF-kappaB in the formation of osteoclasts during development was discovered recently after the generation of knockout mice, which lack the expression of the p50 and p52 subunits. This paper will describe recent studies that reveal an essential role for NF-kappaB signaling in the generation of osteoclasts and that suggest that NF-kappaB may also play a key central role in the activation and survival of osteoclasts in conditions in which osteoclastogenesis is upregulated.