Somatostatin (SST) is a naturally occurring neuropeptide that has multiple modulatory effects on the immune system and the function of synovial cells, as well as anti-angiogenic, antiproliferative and analgesic properties. These unique and diverse properties make this naturally occurring peptide an attractive candidate for use as a therapeutic agent in immune-mediated diseases, particularly in rheumatoid arthritis (RA). In this disease, proliferation of the synovial membrane, angiogenesis and dysregulated immunological activity lead to joint erosion and destruction. Here we review the postulated modes of action of SST in animal models of inflammation, autoimmunity and RA, as well as in humans. We also discuss the wide distribution of SST and its specific receptors, and the various SST analogs available. Results of a pilot study to evaluate the effect of SST analog treatment in refractory RA is discussed, and future directions for treatment and investigation are suggested.