Harold Frost first proposed the existence of several mechanical thresholds in bone, two of which determine whether bone is added to, or lost from, the skeleton. Recent evidence from bone biology helps elucidate the role of osteocytes in determining these mechanical thresholds. Specifically, when mechanical stimuli fall below the resorption threshold, osteocyte apoptosis occurs, followed by bone resorption. Conversely, mechanical loading maintains osteocytes viability, and consequently, no bone is lost. With a greater than customary mechanical stimulus, osteocytes perturbation from pulsatile fluid flow results in release of anabolic factors and subsequent bone formation. Osteocytes also play a pivotal role in bone remodeling in response to alterations in the mechanical environment. In particular, osteocyte apoptosis results in bone turnover in disuse as well as in response to greater than customary mechanical stimuli due to microdamage accumulation. Given the important role of osteocytes in bone modeling and remodeling, these cells provide an ideal target for both drug therapies and exercise to prevent bone fragility.