In vivo regeneration of β cells provides hope for self-renewal of functional insulin-secreting cells following β-cell failure, a historically fatal condition now sustainable only by administration of exogenous insulin. Despite advances in the treatment of diabetes mellitus, the path toward endogenous renewal of β-cell populations has remained elusive. Intensive efforts have focused on elucidating pancreatic transcriptional programs that can drive the division and (trans-)differentiation of non-β cells to produce insulin. A surprise has been the identification of an essential role of the molecular circadian clock in the regulation of competent insulin-producing β cells. In this issue of Genes & Development, work by Petrenko and colleagues (pp. 1650-1665) now shows a requirement for the intrinsic clock in the regenerative capacity of insulin-producing cells following genetic ablation of β cells. These studies raise the possibility that enhancing core clock activity may provide an adjuvant in cell replacement therapies. © 2020 Weidemann and Bass; Published by Cold Spring Harbor Laboratory Press.