The NFκB pathway plays a critical role in the regulation of osteoclast activity, and activation of the pathway is dependent on IκB kinase (IKK), which phosphorylates IκB, targeting it for proteasomal degradation. Pharmacological inhibitors of IKK exhibit anti-inflammatory properties and prevent bone erosions in models of inflammatory arthritis. However, the effects of these agents on osteoblast function and ovariectomy-induced bone loss remain unknown. Here we examined the effects of the IKK inhibitors celastrol, BMS-345541, and parthenolide on bone cell function in vitro and ovariectomy-induced bone loss in vivo. All three compounds inhibited RANKL-induced signaling in osteoclasts, caused osteoclast apoptosis, and inhibited osteoclast formation. Although parthenolide and BMS-345541 had no inhibitory effects on osteoblast function, celastrol prevented IL1β-induced TAK1 activation and inhibited osteoblast growth, differentiation, and bone nodule formation. The selective IKK inhibitors parthenolide and BMS-345541 prevented ovariectomy-induced bone loss by inhibiting osteoclastic bone resorption. We conclude that pharmacological inhibitors of IKK inhibit several critical signaling pathways in osteoclasts necessary for cell survival, formation, and activity in vitro and bone loss in vivo. Accordingly, IKK inhibitors may be of value in the prevention and treatment of bone diseases characterized by increased bone loss such as postmenopausal osteoporosis.