The advent of highly active anti-retroviral therapy (HAART) has dramatically decreased the rate of AIDS-related mortality and significantly extended the life span of patients with AIDS. A variety of metabolic side effects are associated with these therapies, one of which is metabolic bone disease. A higher prevalence of osteopenia and osteoporosis in HIV-infected patients receiving anti-retroviral therapy than in patients not on therapy has now been reported in several studies. Several factors have been demonstrated to influence HIV-associated decreases in bone mineral density (BMD), including administration of nucleoside reverse transcriptase inhibitors (NRTIs). In this article, discussion will focus on the molecular pathogenesis and treatment of HAART-associated osteopenia and osteoporosis. © 2006 New York Academy of Sciences.