Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear receptor that functions as a master transcriptional regulator of adipocyte conversion. During PPARgamma transactivation, multiple signaling pathways interact with one another, leading to the differentiation of both white and brown adipose tissue. Ligand activation of the PPARgamma-RXR heterodimer complex also enhances insulin sensitivity, and this property has been heavily exploited to develop effective pharmacotherapies for the treatment of type 2 diabetes mellitus. PPARgamma is also expressed in stem cells and plays a critical role in mesenchymal stromal cell differentiation and lineage determination events. The many facets of PPARgamma activity within the bone marrow niche where adipocytes, osteoblasts, and hematopoietic cells reside make this molecule an attractive target for pharmacological investigation. Additional findings that osteoblasts can alter energy metabolism by influencing adiposity and insulin sensitivity, and observations of decreased bone turnover in diabetic subjects, underscore the contribution of the skeleton to systemic energy requirements. Studies into the role of PPARgamma in skeletal acquisition and maintenance may lead to a better understanding of the molecular mechanisms governing stromal cell differentiation in the mesenchyme compartment and whether PPARgamma activity can be manipulated to benefit skeletal remodeling events and energy metabolism.