To analyze cell lineage in the pancreatic islets, we have irreversibly tagged all the progeny of cells through the activity of Cre recombinase. Adult glucagon alpha and insulin beta cells are shown to derive from cells that have never transcribed insulin or glucagon, respectively. Also, the beta-cell progenitors, but not alpha-cell progenitors, transcribe the pancreatic polypeptide (PP) gene. Finally, the homeodomain gene PDX1, which is expressed by adult beta-cells, is also expressed by alpha-cell progenitors. Thus the islet alpha- and beta-cell lineages appear to arise independently during ontogeny, probably from a common precursor.