Summary The introduction of highly effective combination regimens of antiretroviral drugs has led in recent years to substantial improvements in morbidity and mortality. As yet immune-based therapies have had little if any impact. However it is clear that eradication of HIV is not achievable with existing anti-HIV drugs and in spite of the major advances there remain many challenges in the clinical management of HIV-infected individuals. These benefits are unlikely to be extended to resource poor countries in the foreseeable future. The barriers are primarily but not only the costs. In resource-rich countries there are concerns about long term toxicities and many people have already exhausted all of the current therapeutic options. There is an urgent need for new drugs, ideally attacking new targets or with no cross resistance to existing drugs, and which are well tolerated and safe, easy to take and cheap. Many important questions still remain unanswered, in particular when to start antiretroviral therapy.