Pituitary tumor initiation and progression are associated with a plethora of genetic imbalances. The role of pituitary trophic status as determinant of neoplastic potential is not clear. The pituitary gland responds to diverse central and peripheral signals by undergoing reversible plastic and functional changes. The resulting hyperplasia/excess hormone production, or involution/hyposecretion in pituitary cells may correlate with the ability to develop pituitary tumors. It is difficult to test this hypothesis, in part due to limitations on the definition of human pituitary cell trophic status and because this organ is not readily accessible for serial histopathological analysis. Therefore, animal models represent the most functional approach to testing this hypothesis. Transgenic mouse models of pituitary tumor transforming gene (PTTG) inactivation or overexpression support the notion that a permissive trophic environment may be required for pituitary tumor formation. Mechanisms underlying changes in pituitary plasticity and their relationship to tumor development may account for the diverse genetic abnormalities observed in pituitary tumors.