Thyroid-stimulating hormone (TSH)-secreting pituitary tumors (TSHomas) are pituitary tumors that constitutively secrete TSH. Molecular mechanisms underlying this abnormality are largely undefined. We have recently created a knockin mutant mouse harboring a mutation (denoted as PV) in the thyroid hormone receptor gene (TR^PV/PV mouse). As these mice age, they spontaneously develop TSHomas. Using this mouse model, we investigated the role of the phosphatidylinositol 3-kinase (PI3K)-AKT signaling pathway in the pathogenesis of TSHomas. Concurrent with aberrant growth of pituitaries, AKT and its downstream effectors—mammalian target rapamycin (mTOR) and p70^S6K—were activated to contribute to increased cell proliferation and pituitary growth. In addition, activation of AKT led to decreased apoptosis by inhibiting pro-apoptotic activity of BAD, further contributing to the aberrant cell proliferation. These results suggest an activated PI3K-AKT pathway could underscore tumorigenesis, raising the possibility that this pathway could be a potential therapeutic target in TSHomas. Indeed, TR^PV/PV mice treated with a PI3K specific inhibitor, LY294002 (LY), showed a significant decrease in pituitary growth. The pro-growth signaling via AKT-mTOR-p70^S6K and cyclin D1/cyclin-dependent kinase (CDK4) were inhibited and pro-apoptotic activity of BAD was increased by LY treatment. Thus, activation of the PI3K-AKT pathway mediates, at least in part, the aberrant pituitary growth, and the intervention of this signaling pathway presents a novel therapeutic opportunity for TSHomas.