The skin secretions of many frogs, including Xenopus laevis, contain caerulein, a peptide related to mammalian cholecystokinin. We have screened a cDNA library prepared from the brain of this frog using a cloned cDNA encoding one of the caerulein precursors as a probe. Two clones were isolated which contained inserts encoding cholecystokinin precursors. It was found that the predicted precursor polypeptides resembled their mammalian counterparts rather than the caerulein precursors from the same species. The corresponding mRNAs of different size encoding the Xenopus cholecystokinin precursors are expressed in brain and in the gastrointestinal tract, but not in skin. The smaller mRNA was also detected in lung. These data demonstrate that a polypeptide homologous to mammalian cholecystokinin precursors was present early in the evolution of vertebrates. The possible evolution of the genes encoding the more complex caerulein precursors is discussed.