Somatostatin was discovered for its ability to inhibit growth hormone (GH) secretion. Later, it was found to be widely distributed in other brain regions, in which it fulfills a neuromodulatory role, and in several organs of the gastrointestinal tract where it can act as a paracrine factor or as a true circulating factor. In mammals, two molecules of 14 (somatostatin 14) and 28 (somatostatin 28) amino acids are the only biologically active members of the family. They originate from a single gene which gives rise to a single propeptide alternately cleaved in different tissues. In 1992, a major breakthrough in our understanding of somatostatin functions was made with the cloning of five different receptor genes (sstr1 to sstr5) which belong to the seven transmembrane domain receptor family. Their closer relatives are opioid receptors. In first approximation, the tissular expression of the sstrs matches quite well with the distribution of somatostatin binding sites in the "classical" targets of the peptide ie brain, pituitary pancreatic islets and adrenals. The pharmacology of GH inhibition is very close to sstr2 binding but other actions of somatostatins have not yet been attributed clearly to a single receptor subtype. All clinically relevant agonists tested so far (octreotide, lanreotide and vapreotide) are selective of sstr2 being less potent on sstr3 and inactive for sstr1 and sstr4. Surprisingly, rat sstr5 displays nanomolar affinities for octreotide and vapreotide while these agonists are only active at much higher concentrations on human sstr5. All five receptors can be more or less efficiently coupled to inhibition of adenylate cyclase activity in transfected cell systems.(ABSTRACT TRUNCATED AT 250 WORDS)