The skeletal system is constantly undergoing turnover in order to create strong, organized structures, requiring the bone breakdown and building properties by osteoclasts and osteoblasts, respectively. However, in pathological disease states, excessive osteoclast activity can cause bone loss leading to increase in morbidity and mortality. Osteoclasts differentiate from macrophages in the presence of various factors. M-CSF is a cytokine that is required to maintain the survival of macrophages. However, RANKL is the critical factor required for differentiation of osteoclasts. RANKL is produced from a variety of different cell types such as osteoblasts and osteocytes. RANKL binds to RANK, its receptor, on the surface of osteoclast precursors, which activates various signaling pathways to drive the transcription and production of genes important for osteoclast formation. The major signaling pathway activated by RANKL–RANK interaction is the NF-κB pathway. The NF-κB pathway is the principle inflammatory response pathway activated by a variety of stimuli such as inflammatory cytokines, genotoxic stress, and other factors. This likely explains the finding that inflammatory diseases often present with some component of increased osteoclast formation and activity, driving bone loss. Determining the signaling mechanisms downstream of RANKL can provide valuable therapeutic targets for the treatment of bone loss in various disease states.