As human beings venture into space in the 21st century, they will be confronted with a "hypodynamic" and thus hostile environment for the bone homeostasis, that could potentially compromise their mobility in general and skeletal strength in particular after landing. From this point of view, space flight studies are especially interesting and intriguing models for scientists. Space studies, however, must not only overcome enormous technical problems but are also limited in size and frequency. Therefore, ground-based models have also been developed to evaluate the effects of skeletal unloading. The most popular model for human studies is prolonged bed rest with normal volunteers, although studies with paraplegics have also been undertaken. In animals, the hindlimb elevation (tail suspension) model simulates space flight models and is well tolerated by the animals with minimal evidence of stress. Although negative calcium balance and bone loss have been observed in all the aforementioned models of skeletal unloading, the exact mechanism(s) by which this occurs are still unknown and mainly speculative.