The traditional view of skeletal homeostasis as a primarily endocrine activity has been expanded in recent years following the identification of direct neural pathways controlling bone homeostasis via central relays. Powerful control over both anabolic and catabolic activities have been isolated to neurons of the hypothalamus, enabling large changes in bone mass to be achieved by minute changes in the levels of these central neural signals. Initiated by studies of leptin and expanding rapidly, the breadth and complexity of this regulatory axis to bone is sure to increase. Critically though, the translation of these findings into therapeutic interventions is likely to present a greater challenge. However, the contribution to our understanding that these initial studies are making indicates an exciting potential to help to alleviate the growing challenge presented by musculoskeletal disease.