The maintenance of skeletal integrity is tightly regulated by two cell types, bone forming osteoblasts and bone resorbing osteoclasts. Although the role of the nervous system in regulating osteoblasts and osteoclasts was identified over a decade ago, the molecular mechanism of skeletal–neural interactions in bone homeostasis has only been studied recently. In particular, the complex roles of axon guidance molecules, such as semaphorins and ephrins, in the bone have been studied extensively. In this review, we highlight the latest advances in determining the functions of semaphorins and ephrins in the establishment and maintenance of the skeletal system, with a focus on the functional interaction between the skeletal and nervous systems.