More insight into the biochemical structure and operation of the somatostatin receptor(s) has been gained in recent years from several approaches. The minimal active structure of the receptor(s) has been identified, and active minisomatostatins have been synthesized. High-affinity binding sites (KDS ranging from 0.1 to 1 nM) have been demonstrated in brain and peripheral organs. In pancreas, stomach, and intestine additional low-affinity sites (or states) have been also suggested Furthermore, cytosolic receptors might be present. Binding affinities of synthetic minisomatostatins, somatostatin-14 and somatostatin-28, show different tissue specificities, suggesting the existence of different receptor subtypes. Two possible interactions of somatostatin with stimulus-secretion coupling in secretory cells have been suggested: a direct activation of the GTP-dependent inhibitory subunit of adenylate cyclase and a distal activation of cytosolic phosphoprotein phosphatases.