The anatomic relationship between serotonergic (5-HT) axons and 5-HT2 receptors in the rat forebrain was determined by a combined analysis of transmitter immunocytochemistry and receptor autoradiography. High densities of 5-HT2 receptors, localized by the ligand N1-methyl-2-125I-LSD (125I-MIL), are found in neocortex and striatum; these regions also receive a dense serotonergic innervation. Regional variations in the density of 5-HT2 receptors and 5-HT axons correspond closely in most, but not all, areas of the forebrain. In somatosensory cortex (SI), the laminar distribution of 5-HT2 receptors closely matches that of 5-HT axons: in particular, a dense band of 5-HT2 receptors in layer Va of SI is in precise register with a dense plexus of fine 5-HT axons. We have also observed a close spatial relationship between 5-HT2 receptors and fine axons in other areas of the forebrain, suggesting that 5-HT2 receptors may be selectively linked to a particular type of 5-HT axon terminal. Since fine axons of this type have been reported to arise from the dorsal raphe nucleus, it appears likely that 5-HT2 receptors may mediate the effects of dorsal but not median raphe projections.