Bone is continuously renewed by bone resorption and subsequent bone formation, a coupling process that maintains the quality as well as the quantity of bone. It is widely accepted that osteoporosis develops when bone resorption exceeds bone formation, and the treatment as well as diagnosis has been targeted to two major cell types, osteoclasts and osteoblasts. Inside bone is a network of the third cell type, osteocytes, the physiological function of which has long remained an enigma. We have developed a transgenic mouse model in which inducible and specific ablation of osteocytes can be achieved in vivo, and here use it to demonstrate that osteocytes serve an important function in regulating the activities of osteoblasts and osteoclasts, while sensing and transducing the mechanical forces exerted on bone. Thus, osteocytes should provide an attractive target for the development of new types of mechanotransduction-based therapeutics and diagnostics for osteoporosis.