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Acromegaly/giantism results from the chronic excess of growth hormone (GH) and insulin-like growth factor-1 (IGF-1), in more than 96% of cases, due to a GH-secreting pituitary adenoma. Primary treatment of choice is transsphenoidal resection of the adenoma. More than 30% to 40% of operated cases require adjunctive forms of treatment, be it pharmacological or radiotherapeutical. The multimodal treatment of acromegaly has resulted in substantial improvements in the quality of life and life expectancy of these patients. We herein present the complex case of a patient with acromegaly due to a mammosomatotrope adenoma, with a germ-line AIP (aryl hydrocarbon receptor–interacting protein) mutation, who had a chronic and protracted course of more than 15 years during which he was treated with surgery, somatostatin receptor ligands, dopamine agonist, and the GH receptor antagonist pegvisomant. At one point, he was able to come off medications and was even found to be transiently GH-deficient, only to develop acromegaly again after a couple of years.