An impressive range of tissues and cells are regulated by mechanical loading, and this regulation is central to disease processes such as osteoporosis, atherosclerosis, and osteoarthritis. However, other than a small number of specialized excitable cells involved in hearing and touch, cellular mechanosensing mechanisms are generally quite poorly understood. A lack of mechanistic understanding of these processes is one of the primary foci of the nascent field of mechanobiology, which, as a consequence, enjoys enormous potential to make critical new insights into both physiological function and etiology of disease. In this review we outline the process in bone by tracing mechanical effects from the organ level to the cellular and molecular levels and by integrating the biological response from molecule to organ. A case is made that a fundamental roadblock to advances in mechanobiology is the dearth of information in the area of pericellular mechanics.