The plasticity of bone to mechanical forces is critical to the success of the muskuloskeletal system. While a link between mechanical forces and skeletal morphology was first recognized by Galileo Galilei in the early 1600’s, our incomplete understanding of mechanotransduction from the organ- down to the molecular/genetic level has crippled our efforts to design effective mechanical (and pharmaceutical) interventions that can promote bone formation without significant side-effects. The current tenet is that mechanical stimuli have to be large in magnitude to elicit an adaptive response. High-impact exercise, when applied for few loading cycles, may indeed be anabolic but among those who are most vulnerable to osteoporosis, low compliance and the possibility of large magnitude forces damaging an already frail skeleton have prevented its widespread use. We have recently shown that even extremely low-magnitude mechanical signals, an order of magnitude below those associated with vigorous exercise, can readily stimulate bone formation and ameliorate mechanical properties. These signals are effective in the growing as well as adult skeleton and may not only be anabolic but also anti-catabolic, even when they are applied for as little as 10 min/day. Interestingly, these low-level vibrations are also sensed in surrounding muscles, highlighting the close functional relation between muskuloskeletal tissues. We have further identified strong interrelations by which gender and genetics influence the efficacy of anabolic as well as catabolic mechanical signals. In particular genetics can greatly affect bone’s plasticity to changes in its mechanical milieu, allowing for the determination of genes underlying this trait. Correlating the molecular response to mechanical stimuli with the induced changes at the tissue level may uncover novel drug targets that are not addressed by current pharmacological interventions and may also enable rapid advances in tissue engineering. In summary, bone’s plasticity to mechanical stimuli is apparent and the identification of the involved genes, molecules, and mechanics will lead to diagnostic, prophylactic, and therapeutic measures (tailored to an individual’s genotype) to combat bone diseases.