Acromegaly/gigantism is characterized by increased levels of growth hormone (GH) and the effector of most of its biological actions, insulin-like growth factor (IGF-1) [1]. In up to 98% of cases, acromegaly is caused by a monoclonal expansion of somatotroph cells that results in a GH-secreting tumor [2], [3]. GH-secreting tumors or somatotrophinomas represent 15% to 20% of all pituitary neuroendocrine tumors (pitNETs) [4]. When they develop before epiphyseal closure, the resulting clinical picture is gigantism, whereas acromegaly is the term used to define cases that develop in adult life [2], [3]. The chronic GH excess results in symptoms and comorbidities that importantly compromise, both the quality of life and life expectancy of the patient [3], [4], [5], [6]. Although the molecular pathogenesis of GH-secreting pitNETs occurring in a hereditary or syndromic context is reasonably well understood, these constitute less than 5% of all acromegaly/gigantism cases [7]. Over 95% of somatotrophinomas occur in a sporadic context, without an identifiable familial or inherited cause. The molecular oncogenesis in this setting is multifactorial, involving the activation of oncogenes and inactivation of tumor suppressor genes at the somatic level, as well as other genetic and epigenetic alterations upsetting the balance between cellular proliferation and apoptosis and resulting in dysregulated hormone secretion [8]. In this review we discuss the complex molecular pathophysiology of sporadic acromegaly.