Activation of the cAMP pathway from the cell surface to the nucleus plays a major role in somatotroph differentiation and growth. This pathway is regulated mainly by the antagonistic hypothalamic hormones GHRH and somatostatin. Several pituitary-specific, as well as ubiquitous, expressed genes are regulated by cAMP in GH-secreting cells. Among them are the GH, GHF-1/Pit-1, c-fos and GHRH-receptor genes. Protein kinase A phosphorylation of Ser133 of the transcription factor cAMP-responsive element binding protein (CREB), seems to play a pivotal role in the activation of the cAMP pathway in normal and tumoral somatotrophs. The oncogenic activating mutations of the G-protein as subunit stimulate transcription and CREB phosphorylation in somatotroph cells. The implications of the nuclear targets of cAMP in the differentiation and growth of somatotrophs are discussed in this review.