Peroxisome proliferator-activated receptor γ (PPARγ) is a ligand-activated transcription factor that belongs to the nuclear hormone receptor superfamily and functions as a heterodimer with a retinoid X receptor by binding to PPAR responsive elements. PPARγ plays an important role in adipocyte differentiation and is activated by long-chain fatty acid, peroxisome proliferators, and thiazolidinedione (TZD). TZD are agonists of PPARγ, act as insulin-sensitizing agents, and are widely prescribed in the management of different conditions characterized by insulin resistance. Osteoblasts and marrow adipocytes derive from common multipotential mesenchymal stem cell (MSC) progenitors. Lineage commitment of MSC is determined by expression and/or activation of specific transcription factors, such as Runx2 and Osterix in the case of osteoblasts, and PPARγ in the case of adipocytes. Many evidences indicate an important role of PPARγ in bone metabolism. Heterozygous PPARγ-deficient (PPARγ +/-) mice exhibit enhanced bone formation with increased osteoblastogenesis. Embryonic stem cells derived from PPARγ +/- mice spontaneously differentiate into osteoblasts. In mice and rats, the activation of PPARγ by TZD treatment, such as rosiglitazone (Rosi), causes bone loss, which results from an increase of marrow adipocytes and a decrease of osteoblasts, leading to a reduction of bone formation rate. Human studies have shown that pre- and post-menopausal women treated with Rosi have an increased risk of fracture compared to women treated with metformin and glyburide. Moreover, the modulation of the PPARγ expression is also implicated in the effects of mechanical loading on bone and in age-related bone loss.