PURPOSE OF REVIEW: Access to first-line antiretroviral therapy in resource-limited settings has increased rapidly in the last 5 years. Newer medicines with greater potency and better safety profiles open the possibility for improving first-line antiretroviral therapy for developing countries. RECENT FINDINGS: Several medicines offer the potential to improve the simplicity, safety and efficacy of first-line antiretroviral therapy in resource-limited settings. These include tenofovir, raltegravir, elvitegravir, rilpivirine and protease inhibitors. A number of clinical questions are outstanding, particularly regarding safety in pregnancy and compatibility with drugs to treat common coinfections including tuberculosis. SUMMARY: Simple, affordable regimens were key to the initial emergency response, but the long-term response to HIV calls for a reconsideration of current treatment options. Preconditions for widespread use in developing countries include affordability, simplicity and answers to relevant research questions. In the absence of strong pharmacovigilance systems, cohort monitoring will be critical to assessing the safety profile of new drugs in such settings.