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Accumulating evidence has contributed to a novel view in bone biology: bone remodeling, specifically osteoblast differentiation, is under the tight control of the central and peripheral nervous systems. Among other players in this neuro-osteogenic network, the neuropeptide Y (NPY) system has attracted particular attention. At the central nervous system level, NPY exerts its function in bone homeostasis through the hypothalamic Y2 receptor. Locally in the bone, NPY action is mediated by its Y1 receptor. Besides the presence of Y1, a complex network exists locally: not only there is input of the peripheral nervous system, as the bone is directly innervated by NPY-containing fibers, but there is also input from non-neuronal cells, including bone cells capable of NPY expression. The interaction of these distinct players to achieve a multilevel control system of bone homeostasis is still under debate. In this review, we will integrate the current knowledge on the impact of the NPY system in bone biology, and discuss the mechanisms through which the balance between central and the peripheral NPY action might be achieved.