The NFκB signal transduction pathway is implicated in the regulation of bone metabolism. This article aims to provide an overview of findings relating to the role of NFκB in bone cell activity and bone remodeling in health and cancer, and highlights the efficacy of pharmacological agents that target key components of NFκB signaling pathways in the reduction of skeletal complications associated with cancer. Lastly, the article speculates on the potential impact of therapeutic use of NFκB inhibitors—alone or in combination with anticancer drugs in clinical practice or development—in the management of “difficult-to-treat” aspects of cancer-induced bone disease such as metastases, tumor immune evasion and pain.