The metabolic syndrome (MetS), a cluster of risk factors for cardiovascular disease and type 2 diabetes, has become an important public health problem. Considerable differences in the prevalence of the MetS in human immunodeficiency virus (HIV)-infected subjects have been reported, as a consequence of several limitations regarding the diagnostic critera for MetS. New evidence suggests that the use of optimal waist cut-off points specific for the various ethnic populations could represent a step forward in overcoming these limitations. Also the use of specific cut-off points for measuring upper trunk fat as an adjunctive criterion of MetS in HIV patients with lipodystrophy could represent an interesting new research topic. Although metabolic disorders have been associated indirectly with highly active antiretroviral therapy (HAART), directly with HIV infection per se or with host conditions, current circumstances could change the framework of MetS in the HIV setting: For example, the aging HIV population and newer, less metabolically toxic antiretroviral drugs. Lipotoxicity and adipokines have been focused as key issues for explaining MetS in HIV patients. Several studies have investigated the pathophysiology of MetS and cardiovascular complications in HIV infection. Evidence shows that both HIV infection per se and HIV-related chronic immune activation despite antiretroviral therapy are critical factors linking MetS and cardiovascular complications. Current epidemiological and pathogenetic data on MetS in HIV infection, prevention strategies and therapeutic options for all MetS components are reviewed in the light of the recent Adult Treatment Panel IV recommendations and the new antiretroviral drugs.