PURPOSE OF REVIEW: Since the introduction of potent antiretroviral therapy, the emphasis in managing HIV patients has changed from treatment and prevention of opportunistic infections to dealing with toxicities of long-term antiretroviral therapy such as bone demineralization. To date, the pathogenic mechanisms underlying the initiation and progression of osteoporosis in HIV patients remain to be elucidated. This review focuses on recent advances in our understanding of the role of both HIV and antiretroviral therapy in driving bone disease and presents an update on current treatment options and new therapeutic agents targeting novel sites. RECENT FINDINGS: Recent studies explored the role of HIV and individual antiretroviral therapy drugs in modifying the phenotype of bone cells. Studies have demonstrated effects on cell differentiation, maturation and function in response to both HIV and its treatment - effects mediated via direct alterations in both cell signaling and gene and protein expression. SUMMARY: Evidence from clinical and cell biological investigations has demonstrated the importance of both HIV and antiretroviral therapy in the emergence of osteoporotic bone disease. Continued efforts aimed at deciphering the molecular basis of metabolic bone disease in HIV patients are necessary to ensure optimal treatment of current patients and to create novel therapeutic interventions.