Bone loss resulting from long-term glucocorticoid therapy is common and clinically relevant. A number of different glucocorticoid-mediated effects are responsible for the reduction in bone density: (i) glucocorticoid-induced direct impairment of osteoblast, osteocyte, and osteoclast function leads to reduced bone remodeling and diminished repair of microdamage in bone; (ii) the effects of parathyroid hormone (PTH) might be more pronounced in the presence of glucocorticoids, whereas vitamin D plays a lesser role in the pathogenesis of steroid-induced osteoporosis; (iii) glucocorticoids antagonize gonadal function and inhibit the osteoanabolic action of sex steroids; and (iv) increased renal elimination and reduced intestinal absorption of calcium lead to a negative calcium balance that has been suggested to promote secondary hyperparathyroidism. From a mechanistic point of view, all of the aforementioned effects have long been considered to be mediated at the molecular level exclusively by genomic actions. However, there is now increasing evidence for the existence of rapid glucocorticoid effects that are incompatible with this classical mode of action. These rapid effects, termed nongenomic effects, are mediated by glucocorticoid interactions with biological membranes, either through binding to membrane receptors or by physicochemical interactions. It is possible, but has yet to be shown, that these effects play a role in the pathogenesis of glucocorticoid-induced osteoporosis.