Tissue injury during chemoradiotherapy presents a substantial clinical challenge. Zhou et al. found that the induction of intestinal stem cell (ISC) proliferation during lethal doses of chemoradiotherapy reduced gut damage in mice bearing intestinal tumours without compromising therapeutic efficacy, and therefore improved the survival of the mice. The SLIT2–roundabout 1 (ROBO1) signalling pathway was shown to have a role in promoting ISC proliferation, and treatment of mice with a short pulse of the WNT agonist R-spondin 1, along with recombinant SLIT2, protected animals from death.