Thiazolidinediones (TZDs) are agonists of the peroxisome proliferator-activated receptor gamma (PPARγ) nuclear transcription factor. Two members of this drug class, rosiglitazone and pioglitazone, are commonly used in the management of type II diabetes mellitus, and play emerging roles in the treatment of other clinical conditions characterized by insulin resistance. Over the past decade, a consistent body of in vitro and animal studies has demonstrated that PPARγ signaling regulates the fate of pluripotent mesenchymal cells, favoring adipogenesis over osteoblastogenesis. Treatment of rodents with TZDs decreases bone formation and bone mass. Until recently, there were no bone-related data available from studies of TZDs in humans. In the past year, however, several clinical studies have reported adverse skeletal actions of TZDs in humans. Collectively, these investigations have demonstrated that the TZDs currently in clinical use decrease bone formation and accelerate bone loss in healthy and insulin-resistant individuals, and increase the risk of fractures in the appendicular skeleton in women with type II diabetes mellitus. These observations should prompt clinicians to evaluate fracture risk in patients for whom TZD therapy is being considered, and initiate skeletal protection in at-risk individuals.