Somatostatin receptors (SSTRs), a family of seven transmembrane (TM) domain G-protein-coupled receptors having five distinct subtypes (termed SSTR1-5), are activated by somatostatin secreted from the nerve and endocrine cells. SSTRs are widely expressed in many tissues, frequently as multiple subtypes that coexist in the same cell. With expressions in a tissue-specific manner, SSTRs are involved in the regulation of secretion of insulin, glucagon, and growth hormone as well as cell growth induced by neuronal excitation in both the central and peripheral nervous systems. The five receptors share common signaling pathways such as the inhibition of adenylyl cyclase, activation of phosphotyrosine phosphatase (PTP), and modulation of mitogen-activated protein kinase (MAPK) through G-protein-dependent mechanisms. Aberrant expression of somatostatin receptors is known to be involved in a large number of human tumors. The human medullary thyroid carcinoma cell line TT expresses all SSTR subtypes. SSTR3 mRNA is detected in the brain and pancreatic islets. SSTR3 uniquely triggers PTP-dependent apoptosis accompanied by the activation of p53 and pro-apoptotic protein Bax, and displays acute desensitization of adenylyl cyclase coupling.