Progressive changes in the distributions of body fat and severe alterations of lipid, glucose and lactate levels challenge the mid and long-term success of highly active antiretroviral therapy of HIV-infection. Both clinical diagnosis of the lipodystrophy syndrome and scientific elucidation of the underlying mechanisms may benefit from a working case definition. In this article, pathophysiological and therapeutic aspects are discussed with reference to physical and metabolic changes. Checkpoints for a practical approach to the patient at risk are given. Specific care and management depend on the predominant alteration, the stage of HIV disease and the medical and antiretroviral history of the individual patient.