p53 promotes the revival of stem cells in the regenerating intestine after severe radiation injury. Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53, but p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Using single-cell RNA-sequencing of the irradiated mouse small intestine, the study found that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. In mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs. Using intestinal organoids, the study showed that transient p53 expression is required for the induction of revival stem cells and is controlled by an Mdm2-mediated negative feedback loop. These findings reveal that p53 suppresses severe radiation-induced GI injury by promoting fetal-like reprogramming of irradiated intestinal epithelial cells. Radiation tolerance of the GI tract limits the effectiveness of radiation therapy for thoracic, pelvic, or abdominal malignancies, such as pancreatic cancer. The radiation tolerance of the GI tract can also be exceeded in radiation accidents at nuclear power plants or after the detonation of a nuclear weapon or radioactive bomb, which can cause a lethal radiation-induced GI syndrome. There are currently no treatments to mitigate radiation-induced GI syndrome that have been approved by the US Food and Drug Administration. Thus, there is a critical need to understand the mechanisms of radiation-induced GI injury and regeneration. During homeostasis, epithelial cell turnover in the intestine is maintained by Lgr5+ crypt base columnar (CBC) cells located at the bottom of intestinal crypts, which self-renew and give rise to differentiated progeny that constitute the intestinal epithelium. The intestinal epithelium can fully recover from acute injury after a single radiation dose that ablates the Lgr5+ CBCs. However, continuous Lgr5+ CBC depletion leads to crypt loss and subsequent regeneration failure, indicating that Lgr5+ CBCs must be replenished after injury to repair the intestinal epithelium. Recent studies support a paradigm in which the progeny of Lgr5+ CBCs, after chemical and radiation injury, undergo de-differentiation to reconstitute fresh Lgr5+ CBCs and regenerate the epithelium. To investigate key signaling pathways that control the reversion of differentiated intestinal epithelial cells into stem cells following severe radiation injury, the study focuses on the tumor suppressor p53. The study performed single-cell RNA-seq (scRNA-seq) and lineage tracing experiments to demonstrate that transient activation of p53 is required to properly reprogram damaged epithelial cells in response to severe radiation injury to promote tissue regeneration. The study found that p53 promotes revSC-mediated regeneration of irradiated intestinal epithelial cells. Thep53 promotes the revival of stem cells in the regenerating intestine after severe radiation injury. Ionizing radiation induces cell death in the gastrointestinal (GI) epithelium by activating p53, but p53 also prevents animal lethality caused by radiation-induced acute GI syndrome. Using single-cell RNA-sequencing of the irradiated mouse small intestine, the study found that p53 target genes are specifically enriched in regenerating epithelial cells that undergo fetal-like reversion, including revival stem cells (revSCs) that promote animal survival after severe damage of the GI tract. In mice with p53 deleted specifically in the GI epithelium, ionizing radiation fails to induce fetal-like revSCs. Using intestinal organoids, the study showed that transient p53 expression is required for the induction of revival stem cells and is controlled by an Mdm2-mediated negative feedback loop. These findings reveal that p53 suppresses severe radiation-induced GI injury by promoting fetal-like reprogramming of irradiated intestinal epithelial cells. Radiation tolerance of the GI tract limits the effectiveness of radiation therapy for thoracic, pelvic, or abdominal malignancies, such as pancreatic cancer. The radiation tolerance of the GI tract can also be exceeded in radiation accidents at nuclear power plants or after the detonation of a nuclear weapon or radioactive bomb, which can cause a lethal radiation-induced GI syndrome. There are currently no treatments to mitigate radiation-induced GI syndrome that have been approved by the US Food and Drug Administration. Thus, there is a critical need to understand the mechanisms of radiation-induced GI injury and regeneration. During homeostasis, epithelial cell turnover in the intestine is maintained by Lgr5+ crypt base columnar (CBC) cells located at the bottom of intestinal crypts, which self-renew and give rise to differentiated progeny that constitute the intestinal epithelium. The intestinal epithelium can fully recover from acute injury after a single radiation dose that ablates the Lgr5+ CBCs. However, continuous Lgr5+ CBC depletion leads to crypt loss and subsequent regeneration failure, indicating that Lgr5+ CBCs must be replenished after injury to repair the intestinal epithelium. Recent studies support a paradigm in which the progeny of Lgr5+ CBCs, after chemical and radiation injury, undergo de-differentiation to reconstitute fresh Lgr5+ CBCs and regenerate the epithelium. To investigate key signaling pathways that control the reversion of differentiated intestinal epithelial cells into stem cells following severe radiation injury, the study focuses on the tumor suppressor p53. The study performed single-cell RNA-seq (scRNA-seq) and lineage tracing experiments to demonstrate that transient activation of p53 is required to properly reprogram damaged epithelial cells in response to severe radiation injury to promote tissue regeneration. The study found that p53 promotes revSC-mediated regeneration of irradiated intestinal epithelial cells. The