New research has shown that two proteins—Slit2 (purported to be involved in cellular migration) and R-spondin 1 (a Wnt agonist)—impart a protective effect on intestinal stem cells (ISCs) in mice treated with high doses of chemoradiation. Indeed, depleting the Slit2 receptor Robo1 resulted in a reduction in ISC number and caused villus hypertrophy. By contrast, administration of R-spondin 1 and Slit2 mitigated ISC loss after chemoradiation in mice. Importantly, manipulating the levels of these proteins did not adversely affect the sensitivity of tumours in ApcMin/+ mice with spontaneous intestinal adenomas, which bodes well for R-spondin 1 and Slit2 as potential adjuvant therapies to reduce gut toxicity in patients with cancer.