Loss of bone during extended space flight has long been a concern that could limit the ability of humans to explore the universe. Surprisingly, the available data do not support the concept that weightlessness leads inexorably to a depleted skeleton unable to withstand the stress of a return to a 1-g environment. Nevertheless, some bone loss does occur, especially in those bones most stressed by gravity prior to flight, which provides confirmation of the proposal formulated over a century ago by Julius Wolff that mechanical stress determines the form and function of bone. Although the phenomenon of bone loss with skeletal unloading, whether by space flight or immobilization or just taking a load off your feet (literally) is well established, the mechanisms by which bone senses load and adjusts to it are not so clear. What actually is the stimulus, and what are the sensors? What are the target cells? How do the sensors communicate the message into the cells, and by what pathways do the cells respond? What is the role of endocrine, factors vs. paracrine or autocrine factors in mediating or modulating the response? None of these questions has been answered with certainty, but, as will become apparent in this review, we have some clues directing us to the answers. Although the focus of this review concerns space flight, it seems highly likely that the mechanisms mediating the transmission of mechanical load to changes in bone formation and resorption apply equally well to all forms of disuse osteoporosis and are likely to be the same mechanisms affected by other etiologies of osteoporosis.