In this study, Ritschka et al. investigated whether cellular senescence might play a role in loss of regenerative capacity during liver regeneration. They show that following partial hepatectomy, the senescence-associated genes p21, p16Ink4a, and p19Arfbecome dynamically expressed in different cell types when regenerative capacity decreases, but without a full senescent response, and that treatment with a senescence-inhibiting drug improves regeneration through targeting aberrantly prolonged p21 expression.