Somatostatin influences motility, secretion, and absorption and often has in vivo a modulating, indirect effect on target cells in the gastrointestinal tract. Knowledge on tissue-specific expression of the five somatostatin receptors (SSTRs), their capacities for internalization and downregulation, their subtype-specific intracellular messengers, and the possibility of forming functionally distinct homodimers or heterodimers, has further complicated the actual in-vivo mechanism of action of somatostatin. This review reports recent in-vivo and in-vitro studies on somatostatin effects on the gastrointestinal tract and pancreas, most of them using a new engineered animal model able to define specific roles of somatostatin and/or its receptor subtypes.SSTR2 knockout mice showed normal circulating gastrin and unchanged acid output, suggesting a high degree of plasticity behind gastric acid secretion. Intestinal inflammation significantly increased somatostatin mRNA in SSTR2 null compared to wild type suggesting that somatostatin mediates inflammation also in SSTR2 null mice. In pancreatic islets of SSTR1-5 null mice no variations of islet size, cellular organization or glucagon or insulin content was shown when compared with null SSTRs and control mice.Although none of the recent findings produced on somatostatin seem ready to be considered for clinical application, recent developments of animal models such as SSTR knockout mice have highlighted promising results to better understand the direct and indirect effects of somatostatin on gastrointestinal tract functions.