Quantitative in vitro autoradiography was used to determine and compare the areal and laminar distribution of the major dopaminergic, adrenergic, and serotonergic neurotransmitter receptors in 4 cytoarchitectonic regions of the prefrontal cortex (Walker's areas 12, 46, 9, and 25) in adult rhesus monkeys. The selective ligands, 3H-SCH- 23390, 3H-raclopride, 3H-prazosin, and 3H-clonidine were used to label the D1 and D2 dopamine receptor subtypes and the alpha 1- and alpha 2- adrenergic receptors, respectively, while 125I-iodopindolol was used to detect beta-adrenergic receptors. The radioligands, 3H-5- hydroxytryptamine and 3H-ketanserin labeled, respectively, the 5-HT1 and 5-HT2 receptors. Densitometry was performed on all cortical layers and sublayers for each of the 7 ligands to allow quantitative as well as qualitative comparison among them in each cytoarchitectonic area. Although each monoamine receptor was distributed in a distinctive laminar-specific pattern that was remarkably similar from area to area, there was considerable overlap among the dopaminergic, adrenergic, and serotoninergic receptors, while subtypes of the same receptor class tended to have complementary laminar profiles and different concentrations. Thus, the D1 dopamine, the alpha 1- and alpha 2- adrenergic, and the 5-HT1 receptors were present in highest relative concentration in superficial layers I, II, and IIIa (the “S” group). In contrast, the beta 1- and beta 2-adrenergic subtypes and the 5-HT2 receptor had their highest concentrations in the intermediate layers, IIIb and IV (the “I” group), while the D2 receptor was distinguished by relatively high concentrations in the deep layer V compared to all other layers (the “D” class). Consequently, clear laminar differences were observed in the D1 vs D2 dopaminergic, the alpha- vs beta- adrenergic, and the 5-HT1 vs 5-HT2 serotoninergic receptor subtypes in all 4 areas examined. The anatomical overlap of different monoaminergic receptors in the same cortical strata suggests that there may be families of receptors linked by localization on common targets, while the complementary laminar distribution of the D1 vs D2, the 5-HT1 vs 5- HT2 and the alpha- vs beta-adrenergic receptors raises the possibility that different subtypes within a given class may have distinctive actions in cortex by virtue of their localization on different cells or possibly different portions of the same cell. Understanding the anatomical arrangement of receptors within the cortical layers may aid in the analysis of monoaminergic modulation of higher cortical function.