The spectrum of drugs used in HIV-infected patients has dramatically changed since triple antiretroviral combinations were introduced, albeit at the expense of some severe adverse events, in 1996. Long term complications of antiretroviral drug exposure, such as HIV lipodystrophy, as well as organ-specific disease of heart and bone are, therefore, a critical issue when designing antiretroviral regimens. Because it is difficult to predict the occurrence of lipodystrophy, and because there is no therapeutic agents able to combat lipodystrophy once established, avoidance of thymidine nucleoside analogues remains the most useful strategy to prevent and treat lipoatrophy; although this approach can worsen dyslipidaemia. Decreasing thymidine analgoue use as well as the availability of new drugs and new drug classes leaded to a reduced likelihood of lipodystrophy development. Metabolic syndrome can and should be assessed as it predicts type 2 diabetes as well as cardiovascular events in HIV-infected individuals. Ongoing HIV replication is a risk factor for serious non-AIDS events, including cardiovascular disease. Therefore, HIV RNA suppression is imperative in all patients on antiretroviral therapy. Finally, HIV-infected adults on antiretroviral therapy, particularly in those receiving a boosted protease inhibitor, have a high prevalence of low bone mineral density. The estimation of fracture risk with the WHO FRAXTM tool deserves further validation in HIV-infected adults. In conclusion, prevention, detection and treatment of various non-infectious comorbidities has become essential for HIV-infected individuals exposed to a life-long antiretroviral therapy and goes beyond the sole management of the lipodystrophy syndrome.