The p53 tumor suppressor maintains the normal cell growth and genomic stability by launching cell cycle arrest, DNA repair, or apoptosis in response to DNA damage or other forms of cellular stress. Recent studies also suggest that p53 is capable of much broader cellular functions, including the regulation of energy metabolism and autophagy. However, the role of p53 in regulating lipid metabolism is less well understood. Here we report a novel function of p53 in regulating lipid metabolism. Loss of p53 leads to lipid accumulation in both mouse embryonic fibroblast (MEF) cells and mouse liver. Upon high-fat diet (HFD) treatment, p53 knockout mice exhibit marked obesity and hepatic lipid accumulation. Mechanistically, p53 regulates lipid metabolism through transcriptionally regulating aromatase, a key enzyme that converts androgens to estrogens. The importance of aromatase in mediating p53's function in regulating lipid metabolism is revealed by the observation that transgenic expression of aromatase almost completely reverses the promoting effect of p53 deficiency on lipid accumulation in mouse liver.