GUCY2C paracrine signaling plays an essential role in homeostatic mechanisms maintaining the crypt-villus axis in intestine. Radiation disrupts those mechanisms, inducing toxicity underlying the potentially lethal gastrointestinal (GI) syndrome. Expression of the GUYC2C receptor (green) and its paracrine hormone uroguanylin (red) was preserved in small intestine 48 hours following exposure of mice to toxic doses of radiation. These results suggest a role for the GUCY2C signaling axis in compensatory responses to intestinal radiation. Further, they support the utility of oral GUCY2C ligands to prevent and treat the radiation-induced GI syndrome. For details, see article by Li and colleagues on page 5095.