In recent years the demonstration that human pituitary adenomas are monoclonal provides further evidence of genomic mutations occurring in the progenitor cell that subsequently undergoes clonal expansion. Up to now the only mutations identified in a significant proportion of pituitary tumors, and particular in GH-secreting adenomas, occur in the Gsalpha gene and cause constitutive activation of the cAMP pathway. Subsequent studies revealed that these mutations are associated with several feedback mechanisms that, at least in part, counteract the oncogenic potential of mutant Gsalpha. As far as the promoting agents are concerned, several lines of evidence indicate that in pituitary tumors growth factors or their receptors may be overexpressed at variable levels. The contribution of these defects in human pituitary tumorigenesis remains to be established.