The pancreas is a complex organ comprising the exocrine pancreas that produces digestive enzymes and the endocrine pancreas that produces the metabolism-regulating hormones insulin and glucagon. For many years, embryologists have been trying to understand how the developmental process gives rise to these two functionally distinct tissues within a single organ. Prior work has shown that expression of the transcription factor Neurogenin3 is both necessary and sufficient to trigger differentiation of primordial pancreatic cells into endocrine cells. Those studies also suggested that cells destined for the endocrine lineage switch very rapidly to high levels of Neurogenin3 expression. Now, however, Vanderbilt Basic Sciences researchers Christopher Wright and Mark Magnuson and their laboratories report that a stable population of cells expressing very low levels of Neurogenin3 appears at the beginning of the second phase of pancreatic development. Using an elegant mouse model that enables visualization of low levels of Neurogenin3 transcription, the investigators further show that these cells serve as a stable progenitor population that divide to yield either two new progenitor cells or two cells that will commit to endocrine cell differentiation with high Neurogenin3 expression. These studies not only provide important information on the basic development of a key organ in the body, they also add to our understanding of the process of stem cell differentiation, knowledge that is critical for our eventual therapeutic application of stem cells. The work is published in the journal Genes and Development [M. E. Bechard, et al. (2016) Genes Dev., 30, 1852].