In utero exposure of the embryo and fetus to radiation has been implicated in malformations or fetal death, and often produces lifelong health consequences such as cancers and mental retardation. Here we demonstrate that deletion of a G-protein-coupled purinergic receptor, P2Y 14, confers potent resistance to in utero radiation. Intriguingly, a putative P2Y 14 receptor ligand, UDP-glucose, phenocopies the effect of P2Y 14 deficiency. These data indicate that P2Y 14 is a receptor governing in utero tolerance to genotoxic stress that may be pharmacologically targeted to mitigate radiation toxicity in pregnancy.