Pituitary adenomas are common monoclonal neoplasms accounting for approximately one-fifth of primary intracranial tumors. Prolactin-secreting pituitary adenomas (prolactinomas) are the most common form of pituitary tumors in humans. They are associated with excessive release of the hormone prolactin and increased tumor growth, giving rise to severe endocrine disorders and serious clinical concerns for the patients. Recent studies indicated that the activin/TGF-beta family of growth factors plays a prominent role in regulating pituitary tumor growth and prolactin secretion from anterior pituitary lactotrope cells. Furthermore, these studies highlighted the tumor suppressor menin and the protein Smads as central regulators of these biological processes in the pituitary. Alterations in the activin/TGF-beta downstream signaling pathways are critical steps towards tumor formation and progression. This chapter will review the role and intracellular molecular mechanisms of action by which activin, TGF-beta, Smads and menin act in concert to prevent pituitary tumor cell growth and control hormonal synthesis by the anterior pituitary.