A total of 5 somatostatin (SS) receptors have been characterized, cloned, and transfected into various cell types which have recently been used to discern peptide ligands displaying high degrees of selectivity for binding to types 2, 3, and 4. These have now allowed us to examine which receptor(s) is involved in SS inhibition of glucose-stimulated rat pancreatic insulin release. The type 4 selective ligand, DC-23-99, which had little affinity for receptor types 1, 2, or 5, was at least equipotent to SS in preventing insulin release. In contrast, the type 3 selective peptide, DC-25-20, was totally devoid of inhibitory effects. Peptides, such as NC-8-12, which have extremely high affinity for type 2 receptors but far less for types 1, 3, 4 and 5, were considerably less potent than SS in this assay. Thus, 2 major inhibitory physiological functions of SS on GH (type 2) and insulin release appear to be mediated by entirely different receptor types.