Somatostatin (SST) is a multifunctional peptide with two biologically active forms, SST-14 and SST-28, which are synthesized in neurons throughout the brain as well as in peripheral tissues such as the pancreas and the gut. SST exerts a diverse array of effects that include inhibition of endocrine secretion, modulation of neurotransmission, and regulation of cell proliferation by stimulating a family of five G-protein-coupled receptors. Somatostatin receptor SST5 is an inhibitory G protein-coupled receptor that exerts a strong cytostatic effect on various cell types. In mice, SST5 mediates somatostatin inhibition of pancreatic insulin secretion and contributes to the regulation of glucose homeostasis and insulin sensitivity. In addition, deficiency of SST5 leads to subtype-selective sexually dimorphic changes in the expression of both brain and pancreatic somatostatins.