The high-mobility group (HMG) protein A2 has been studied mostly in the mouse where its function seems critical for embryonic cell growth and adipogenesis, leading to a pygmy phenotype with greatly reduced fat tissue in homozygous knock out mice. We showed recently that among the major HMG proteins, HMGA2 is highly expressed in two human embryonic stem (hES) cell lines. Here, we employed siRNA technology in combination with quantitative reverse transcriptase polymerase chain reaction, stem cell-specific microarray analyses, and cell proliferation assays in order to probe into HMGA2's role(s) in pluripotent hES cells. Our results establish HMGA2 as a regulator of human genes linked to mesenchymal cell differentiation, adipogenesis, and hES cell growth.