The recent clinical use of potent HIV-1 drugs, including nucleoside reverse transcriptase inhibitors (NRTIs) and non-peptidic viral protease inhibitors (PIs), and their combinations, termed highly active antiretroviral therapy (HAART), has dramatically reduced the infection-related mortality of AIDS patients, but it is associated with severe metabolic adverse events such as lipodystrophy syndrome, dyslipidaemia, insulin resistance and diabetes mellitus. The aetiology of this syndrome and metabolic alterations appear to be multifactorial, including HIV drug inhibitory effects on adipocyte differentiation, alteration of mitochondrial functions in adipocytes and altered leptin, adiponectin and cytokine expression in adipose tissue of patients. Adipose tissue may thus be a central regulator in disorganized lipid metabolism and insulin resistance associated with antiretroviral therapy, and we propose in this review to explore how adipose tissue may be a target, but also an actor, in the aetiopathogenesis of the lipodystrophy syndrome.