Combination antiretroviral therapy (ART) has dramatically altered the prognosis of individuals infected with HIV. In the past 5 years there has been a concerted effort to increase access to ART in the developing world. The evidence to date suggests that adherence to therapy and clinical outcomes in developing world programmes are at least the equal of those observed in developed countries. Although access to first-line therapy is reasonably well established, there is a substantial and unacceptable mortality rate in the first 6 months after initiation of ART, particularly in those with low CD4 cell counts and late-stage disease. Failure of first-line ART is inevitable in a proportion of patients. Access to second-line ART regimens in developing countries is problematic, mainly because of the expense of HIV protease inhibitors (PIs). Access to second-line ART may be facilitated by novel strategies using the existing recommended agents or by the use of new agents or classes. Refinement of programmes in the developing world must be underpinned by the same rigorous scientific research effort that has characterized the success of the effort in the developed world. Therefore, the funding bodies responsible for the roll-out of antiretroviral access across the globe must mandate, incorporate and fund clinical research as an intrinsic aspect of combination ART roll-out programmes.