The intestinal epithelium continually self-renews and can rapidly regenerate after damage. Lgr5 marks mitotically active intestinal stem cells (ISCs). Importantly, intestinal homeostasis can be maintained after depletion of Lgr5⁺ cells due to the activation of Lgr5⁻ reserve ISCs. The Lgr5⁻ ISC populations are thought to play a similar role during intestinal regeneration following radiation-induced damage. We tested this regeneration hypothesis by combining depletion of Lgr5⁺ ISCs with radiation exposure. In contrast to the negligible effect of Lgr5⁺ ISC loss during homeostasis, depletion of Lgr5⁺ cells during radiation-induced damage and subsequent repair caused catastrophic crypt loss and deterioration of crypt-villus architecture. Interestingly though, we found that crypts deficient for Lgr5⁺ cells are competent to undergo hyperplasia upon loss of Apc. These data argue that Lgr5⁻ reserve stem cells are radiosensitive and that Lgr5⁺ cells are crucial for robust intestinal regeneration following radiation exposure but are dispensable for premalignant hyperproliferation.