P53 is most well-known for its tumor suppressive function in differentiated cells. Its activities in embryonic stem cells (ESCs) are, however, less well understood. For many years it was thought that p53 is not active at all in ESCs and unable to elicit a DNA damage response in this cell type. In the last few years, it emerged that p53 may have some functions in ESCs. Nevertheless, it remained a mystery how its activity is controlled in ESCs. A recent report demonstrates that p53 activity is regulated by a novel RNA-containing negative feedback loop that promotes apoptosis specifically in ESCs. This study not only demonstrates unequivocally that p53 is active in ESCs, it further illustrates a novel mechanism of gene regulation-by protein coding RNAs. © 2015 Blattner.