Hypothalamic growth hormone-releasing hormone (GHRH) stimulates growth hormone (GH) production and somatotroph proliferation by binding to a seven transmembrane-domain receptor, linked to Gs. Gs stimulates production of cyclic adenosine 3'-5'-monophosphate (cAMP) and hence activation of protein kinase A (PKA). A subgroup of pituitary somatotroph adenomas has been demonstrated, which has constitutive activation of Gs, with reduced in vitro responsiveness to agents that stimulate Gs. Subsequently, somatotroph adenomas have been identified, which have activating mutations of Gs (gsp). However, there are no clear clinical or biochemical phenotypic characteristics that enable gsp-positive and gsp-negative tumors to be differentiated from one another. Gsp mutations occur in 35% to 40% of somatotroph adenomas in caucasians, but have a much lower reported prevalence of 4% to 9% in the Japanese population. G-protein mutations also occur in clinically nonfunctioning pituitary tumors and, rarely, in corticotroph adenomas. There is little direct evidence at present to suggest that the gsp mutation has a primary oncogenic role in the pathogenesis and function of pituitary tumors. Further functional studies are needed. The gsp mutation is probably one of several oncogenic mutations required for pituitary tumor development.