Despite its importance for generating and maintaining a healthy and broad T cell repertoire, the thymus is exquisitely sensitive to acute damage. Marked thymic involution occurs in response to stimuli as diverse as infection, stress, pregnancy, malnutrition, drug use and cytoreductive chemotherapy. However, the thymus also has a remarkable capacity for repair, although this regenerative capacity declines with age. Endogenous thymic regeneration is a crucial process that allows for the recovery of immune competence after acute damage and delay to this recovery can have important clinical effects. Until recently, the mechanisms that drive endogenous thymic regeneration were not well understood, but recent work in mice has revealed multiple distinct pathways of regeneration and the molecular mechanisms that trigger these pathways after damage. In this Review, we discuss the effects of different types of damage to the thymus, with a focus on an emerging body of work in mice that provides insight into the cellular and molecular mechanisms that regulate endogenous tissue regeneration in the thymus. We also highlight some of the clinical challenges that are presented by dysregulated thymic regeneration.