The introduction of highly active antiretroviral therapy (HAART) has dramatically improved the long-term prognosis of human immunodeficiency virus (HIV)-infected patients, but several abnormalities of lipid and glucose metabolism have recently been reported with increasing frequency in patients receiving potent new antiretroviral combinations. Although a rare occurrence before the HAART era, insulin resistance has now been described as an important component of the lipodystrophy syndrome, including body fat redistribution, hypertriglyceridemia, hypercholesterolemia, hyperinsulinemia, and hyperglycemia. The etiology of such abnormalities remains unclear; but protease inhibitors and, to a lesser extent, nucleoside reverse transcriptase inhibitors are believed to contribute to the pathogenetic mechanism. The potential clinico-pathological consequences of glucose metabolism dysregulation, such as atherosclerosis and coronary heart disease, all make the management of insulin resistance and diabetes mellitus a challenge in the management of HIV-infected patients. Because of similarities to pathogenesis and clinical presentation of type 2 diabetes mellitus, treatment of HAART-associated hyperinsulinemia and hyperglycemia could follow the recommendations of the American Diabetes Association, but the most effective and safe management of these metabolic alterations is still unknown. The present review evaluated the most recently published data about incidence, risk factors, pathogenesis, clinical complications, and management of glucose disorders associated with antiretroviral therapy.