Mechanical loading of the skeleton is essential for the development, growth, and maintenance of strong, weight-bearing bones. Bone strength is plastic and can be modulated in adults, as illustrated by the increased bone mass in the playing arms of athletes as compared with their nonplaying arms. Our studies have shown that mechanical loading improves bone strength by inducing bone formation in regions of high strain energy. Therefore, bone tissue has a mechanosensing apparatus that directs osteogenesis to where it is most needed to increase bone strength. The most likely sensors of mechanical loading are the osteocytes, which are visco-elastically coupled to the bone matrix so that their biological response increases with loading rate; thus, increasing loading frequency improves the responsiveness of bone to loading. The osteocyte-specific protein sclerostin, an inhibitor of the Wnt signaling pathway, appears to be one of the mediators of the mechanical loading response. Mechanical loading suppresses osteocyte sclerostin secretion, which allows Wnt signaling-dependent bone formation to occur. Intracellular calcium signaling, adenosine triphosphate signaling, and signaling through second messengers, such as prostaglandins and nitric oxide, precede sclerostin secretion. Stretch-activated ion channels and focal adhesion proteins may play a role in triggering these pathways upstream of sclerostin. In particular, focal adhesion kinase and proline-rich tyrosine kinase 2 appear to be sensors of mechanical loads in bone cells.