Adipose tissue (AT) is recognized as key contributor to the systemic insulin resistance and overt diabetes seen in metabolic syndrome. Acromegaly is a disease characterized by excessive secretion of growth hormone (GH) and insulin-like growth factor I (IGF-I). GH is known both for its action on AT and for its detrimental effect on glucose metabolism and insulin signaling. In active acromegaly, while body fat deports are diminished, insulin resistance is increased. Early studies have demonstrated defects in insulin action, both at the hepatic and extrahepatic (i.e., muscle and fat) levels, in active disease. This review discusses recent data suggesting that AT inflammation, altered AT distribution, and impaired adipogenesis are potential mechanisms contributing to systemic insulin resistance in acromegaly.