Somatostatin (somatotropin release inhibitory factor, SRIF) and the related cortistatin (CST) are multifunctional peptide molecules attributed with neurohormone, neurotransmitter/modulator, and autocrine/paracrine actions. The physiological responses of SRIF and CST are mediated by five widely distributed G protein-coupled receptors (sst1-5) which have been implicated in regulating numerous biological processes. Much of the information on the effects of somatostatin has been gained through pharmacological studies with analogs and antagonists. The possibility of targeted mutagenesis in the mouse has resulted, over the last 10 years, in the generation of mouse models which genetically lack somatostatin ligands or receptors. We will review here the mouse models generated, the studies undertaken with them, and what has been learned so far.