Acromegaly is characterized by sustained elevation of circulating growth hormone (GH) and insulin-like growth factor I (IGF-I), and is clearly associated with increased morbidity and overall mortality mainly due to cardiovascular, metabolic, and respiratory diseases. Although cancer-related mortality varies widely amongst retroperspective studies, it appears to be consistently elevated mainly in patients with uncontrolled disease. We review individual tumor types including neoplasms of the colon, breast, prostate, and thyroid where in vitro, animal studies, and studies in non-acromegalic cancer patients have established a role for the GH/IGF-I axis in tumor progression and possibly initiation. We highlight deficiencies in data in acromegalic patients where the evidence is less convincing. Instead, we explore the hypothesis that acromegaly, independent of hormone secretion, is a disease that heralds genetic and/or epigenetic alterations predisposing to cancer risk elsewhere.