Pancreatic polypeptide (PP) is released from pancreatic islets after meals or in response to stress. Although PP exhibits a wide spectrum of biological effects, few, if any, are mediated by a direct action of PP on its ultimate target organ. Recently, PP receptors have been identified in areas of the brain with an incomplete blood-brain barrier suggesting that PP may act indirectly through the central nervous system. In the present study, we sought to identify peripheral PP binding sites using an in vivo radioreceptor assay and in vitro autoradiography. Using these techniques, we have identified saturable binding sites for PP in the zona fasciculata, zona reticularis, and the medulla of the rat adrenal gland. We have characterized these sites using equilibrium analysis of membrane-radioligand binding and by quantitative autoradiography of radioligand binding to frozen tissue sections. Binding of PP to these sites is saturable, of high affinity, and specific as well as time, temperature, and membrane dependent. Moreover, PP binds to these putative receptor sites in vivo at physiological concentrations. Many of the actions of PPs have been demonstrated to be indirect. Because PP receptors have been identified in the brain and now in the adrenal gland, we suggest that some of the effects of PP may be mediated through direct and indirect modulation of the brain and adrenal axis.