The cloning of five members of the somatostatin receptor family, sst 1-sst 5, as well as two isoforms of the somatostatin receptor 2, sst 2A and sst 2B, enabled us to generate specific anti-peptide antisera against unique sequences in the carboxyl-terminal tail of each somatostatin receptor subtype. We used these antibodies in multicolor immunofluorescent studies aimed to examine the regional and subcellular distribution of somatostatin receptors in adult rat brain. Several findings are notable: The cloned sst 1 receptor is primarily localized to axons, and therefore most likely functions in a presynaptic manner. The cloned sst 2 receptor isoforms exhibit strikingly different distributions, however, both sst 2A and sst 2B are confined to the plasma membrane of neuronal somata and dendrites, and therefore most likely function in a postsynaptic manner. The cloned sst 3 receptor appears to be excluded from ‘classical’ pre- or postsynaptic sites but is selectively targeted to neuronal cilia. The cloned sst 4 receptor is preferentially distributed to distal dendrites, and therefore most likely functions postsynaptically. The cloned sst 5 receptor was not detectable in the adult rat brain, however, prominent sst 5 expression was found in the pituitary. Furthermore, sst 1-containing axons either co-contained somatostatin or were closely apposed by somatostatin-positive terminals in a regional-specific manner. Neuronal somata and dendrites containing either sst 2A, sst 2B or sst 4 were found to exist in close proximity, although not necessarily synaptically linked, to somatostatin-positive terminals. Together, in the central nervous system the effects of somatostatin are mediated by several different receptor proteins which are distributed with considerable regional overlap. However, there appears to be a high degree of specialization among somatostatin receptor subtypes with regard to their subcellular targeting. This subtype-selective targeting may be the underlying principal of organization that allows somatostatinergic modulation of neuronal activity via both pre- and postsynaptic mechanisms.