For decades, the processes that couple bone architecture and mass to function have been investigated and characterized. It is well known, and now well accepted, that increases in exercise and loading of bone are associated with increased bone mass, and that disuse induces osteopenia. However, the mechanisms by which disuse leads to bone loss remain poorly understood, even in the 21st century. Clearly, the skeleton is able to perceive and respond to some general input(s) generated, or lost, as a consequence of mechanical unloading of bone that are distinct from habitual activity, so called functional adaptation. It is the focus of this paper to evaluate the evidence underlying roles for genetics, osteocytes, and interstitial fluid flow in mediating disuse osteopenia.