Cyclic AMP (cAMP) mediates the hormonal stimulation of a number of eukaryotic genes by directing the protein kinase A (PK-A)-dependent phosphorylation of the transcription factor CREB. Somatostatin is one such gene known to be transcriptionally activated by cAMP via CREB. In view of the role somatostatin plays in the regulation of neocortical development, we examined the early expression of CREB mRNA and protein (from E10 to E14) in the rat neocortex by in situ hybridization and immunocytochemistry. mRNA for CREB was detected in all layers of the developing neocortex from E10 to E14. CREB immunoreactivity (CREB-IR) was also observed in most cortical cells by E10. However, the number of CREB-immunoreactive nuclei decreased thereafter, and on E14 there were immunoreactive cells only in the preplate. A moderate amount of somatostatin mRNA was observed on E16 in layer I, which is produced from the preplate. This stage specific expression of the CREB protein in the developing neuroepithelium suggests that by regulating transcription of some peptides including somatostatin, CREB plays a role in cortical development.