The distribution of immunoreactive cholecystokinin, substance P, [Met]enkephalin, [Leu]-enkephalin and dynorphin was determined in the cerebral cortex of the human brain post mortem. Peptide radioimmunoassays in three selected zones of the cortical gray mantle (frontal, temporal, occipital) revealed significant regional differences, prompting to the development of a new dissection procedure for the complete mapping of peptide-like materials throughout the entire cerebral cortex. For this purpose, frozen cerebral hemispheres were cut rostrocaudally in 21 verticofrontal serial sections, from which the cortical gray matter was divided into 4-5 distinct zones. The peptides could be measured in each of the 93 dissected pieces of tissue, but their distribution was uneven. The most abundant was cholecystokinin, particularly in the anterior part of the frontal lobe and in the temporal cortex, where its levels reached 0.5 ng/mg of tissue. The regional distribution of cholecystokinin resembled that of substance P with a decreasing gradient from the frontal to the occipital pole, but absolute levels of substance P were hardly one tenth of cholecystokinin levels. The mean concentrations of the three opioid peptides were even less than those of substance P, and their regional distributions were markedly different. [Met]Enkephalin was concentrated in the occipital cortex, and [Leu]enkephalin in the temporal cortex. Dynorphin was the least abundant, even in the temporal cortex where the highest levels were found. The widespread and heterogeneous distribution of these peptides strongly suggests that each of them exerts specific functions in the human cerebral cortex.