Both cellular and systemic metabolism of lipids are paramount for homeostasis, and their malfunction leads to devastating pathologies. Recently, exciting findings have linked the p53 tumor suppressor to the regulation of lipid metabolism. Here, we summarize these findings showing a clear role for p53 in enhancing lipid catabolism while inhibiting its anabolism. We also describe the multitude of genes regulated by p53 that participate in or regulate systemic lipid transport. From the compilation of available data a scenario is emerging in which p53 regulates genes involved in lipid metabolism - both in a cancer-preventive effort and, intriguingly, as a means to prevent atherosclerosis. Thus, by regulating lipid metabolism, p53 fights the two major causes of death worldwide - atherosclerosis and cancer.