Determining the signalling pathways that direct tissue expansion is a principal goal of regenerative biology. Vigorous pancreatic beta-cell replication in juvenile mice and humans declines with age, and elucidating the basis for this decay may reveal strategies for inducing beta-cell expansion, a long-sought goal for diabetes therapy. Here we show that platelet-derived growth factor receptor (Pdgfr) signalling controls age-dependent beta-cell proliferation in mouse and human pancreatic islets. With age, declining beta-cell Pdgfr levels were accompanied by reductions in beta-cell enhancer of zeste homologue 2 (Ezh2) levels and beta-cell replication. Conditional inactivation of the Pdgfra gene in beta-cells accelerated these changes, preventing mouse neonatal beta-cell expansion and adult beta-cell regeneration. Targeted human PDGFR-a activation in mouse beta-cells stimulated Erk1/2 phosphorylation, leading to Ezh2-dependent expansion of adult beta-cells. Adult human islets lack PDGF signalling competence, but exposure of juvenile human islets to PDGF-AA stimulated beta-cell proliferation. The discovery of a conserved pathway controlling age-dependent beta-cell proliferation indicates new strategies for beta-cell expansion.