Thiazolidinediones, also known as glitazones, are insulin-sensitizing medications that account for approximately 21% of oral antihyperglycemic drugs used in the US. Although the main therapeutic effects occur in adipose tissue, muscles and the liver, studies suggest effects in bone as well. Currently, two thiazolidinediones are marketed in the US—rosiglitazone and pioglitazone—and several others are under investigation. This Review examines the evidence regarding the effects of thiazolidinediones on skeletal health. These drugs appear to trigger preferential differentiation of mesenchymal stem cells into adipocytes rather than osteoblasts, leading to decreased bone formation and increased adipogenesis. Although only a few small, randomized studies have examined the effects of thiazolidinediones on bone in humans, the available data suggest that these agents contribute to bone loss in postmenopausal women; the relationship is less clear in men. On the basis of this limited evidence, the absolute increase in fracture risk associated with thiazolidinediones seems to be small. Pending data from future randomized, controlled trials of the association between thiazolidinediones and low bone mass, prescribers should consider use of these drugs as a risk factor for the development of osteoporosis in postmenopausal women.