Glucocorticoids (GCs) are efficient drugs that are used to treat various immune-mediated diseases, but their long-term administration is associated with multiple metabolic side effects, including osteoporosis. Molecular analyses of the mechanisms exerted by the GC receptor have resulted in the development of GC receptor agonists that selectively repress or activate GC target genes. This review summarizes the cellular and molecular effects of GCs on bone cells and highlights the critical signaling pathways that may evolve into future therapeutic strategies.