Mechanical loading is of pivotal importance in the maintenance of skeletal homeostasis, but the players involved in the transduction of mechanical stimuli to promote bone maintenance have long remained elusive. Osteocytes, the most abundant cells in bone, possess mechanosensing appendices stretching through a system of bone canaliculi. Mechanical stimulation plays an important role in osteocyte survival and hence in the preservation of bone mechanical properties, through the maintenance of bone hydratation. Osteocytes can also control the osteoblastic differentiation of mesenchymal precursors in response to mechanical loading by modulating WNT signaling pathways, essential regulators of cell fate and commitment, through the protein sclerostin. Mutations of Sost, the sclerostin-encoding gene, have dramatic effects on the skeleton, indicating that osteocytes may act as master regulators of bone formation and localized bone remodeling. Moreover, the development of sclerostin inhibitors is opening new possibilities for bone regeneration in orthopedics and the dental field.