The molecular pathogenesis of pituitary disorders is complex and has been explored in animal models and human subject studies. Hormone deficiencies are largely caused by mutations in transcription factors required for pituitary differentiation. Early developmental genes (Rpx, Lhx3, Lhx4, Pitx2) pleiotropically affect multiple pituitary hormones and adjacent physical structures, whereas genes determining specific pituitary lineages (including Prop1, Pit1, SF1, DAX1, Tpit) are involved in single or combined hormone deficiencies. Excess hormone secretion is mostly associated with monoclonal pituitary adenomas. Genes identified for familial pituitary tumor syndromes affect transcription (MEN1) and hypothalamic hormone signaling (CNC1, gsp). Murine gene-disruption studies (Rb, p27, p18) implicate cell-cycle regulatory genes, some of which have altered expression in most human pituitary tumors (p16, p27). Aberrant expression of PTTG, a mammalian securin homolog, can lead to chromosome missegregation, an early step in multistep pituitary tumor progression. Excess hypothalamic trophic hormones lead to pituitary hyperplasia and hormone excess, whereas alterations in hypothalamic hormone receptor genes are uncommon.