Stem cells recover from injury by tissue dedifferentiation, not from dedicated reserves Tissues with high intrinsic turnover, such as the skin and intestinal lining, rely on resident stem cells, which generate all native cell types. Intestinal stem cells (ISCs) are highly sensitive to damage, although they recover quickly. It is unclear whether this recovery (i.e., regeneration) occurs from less sensitive pools of “reserve” stem cells ( 1 ) or whether ISC progeny undergo “reverse” differentiation into stem cells ( 2 ). Recent studies in diverse organs highlight that dedifferentiation of specified cell types is a pervasive and dominant means for tissue regeneration. The findings have broad implications because all tissues experience some cell attrition over a lifetime, and knowing how tissues replenish those losses may help in preventing or treating organ failure. Moreover, it remains unclear whether incomplete differentiation, a common feature of cancer, reflects normal tissue plasticity, and it is unclear whether stem cells that arise by dedifferentiation may spawn cancers.