All pancreatic cell types, including insulin-producing β-cells, arise from pancreatic progenitors during embryonic development, but whether the adult pancreas contains β-cell progenitors remains a controversial issue. Using fate-mapping studies in mice, Maike Sander and colleagues (p. 653) now demonstrate that cells positive for Sox9 give rise to β-cells during embryogenesis, but not in the normal or injured adult pancreas. They generated Sox9CreERT2 mice in which Sox9-expressing cells can be accurately and temporally labelled. Lineage tracing shows that these cells can generate all pancreatic lineages during embryogenesis. By contrast, they report, endocrine and acinar cell neogenesis from Sox9-positive cells does not occur in the adult pancreas. Using partial duct ligation (PDL) to induce pancreatic injury, they also show that Sox9-positive cells do not generate β-cells following injury; PDL initiates pre-endocrine programs but not complete β-cell differentiation. Given the increasing use of PDL as a model to study β-cell regeneration, these studies provide important insights into the specification and regeneration of β-cells.