The introduction of highly active antiretroviral therapy (HAART) including nucleoside reverse transcriptase inhibitors (NRTI) and protease inhibitors (PI) has dramatically improved the morbidity and mortality in HIV-infected patients. Unfortunately, HAART has been associated with several side effects among which the development of lipodystrophy syndrome remains a major clinical issue. It is characterized by fat redistribution dominated by peripheral fat loss and complex metabolic alterations including dyslipidemia and insulin resistance. Dissection of the pathogenesis of the lipodystrophy syndrome is hampered by several factors: all HIV-patients receiving HAART have a chronic and often advanced illness with impact on metabolism and energy homeostasis. Secondly, almost all patients are receiving various combinations of drugs that simultaneously reduce viral replication and restore the immune system. Recently, more detailed clinical studies, experiments using animal models and in vitro systems have been successfully used to elucidate important pathogenic aspects. At the same time, partial reversion of fat loss and metabolic disturbances in HIV-patients could be achieved by omitting components of HAART or administration of metabolically active drugs. Here, we will summarize the current knowledge about the molecular alterations that are induced by antiretroviral therapy and possibly contribute to the lipodystrophy syndrome. Specific attention will be given to the role of NRTI and PI on adipocyte development, function, and mitochondrial integrity leading to fat loss, fat accumulation, and increase of serum lipids.