The development of drugs for HIV infection began soon after the virus was discovered 25 years ago. Since then, progress has been substantial, but numerous uncertainties persist about the best way to manage this disease. Here we review the current treatment options, consider novel mechanisms that can be exploited for existing drug targets, and explore the potential of novel targets. With a view to the next quarter century, we consider whether drug resistance can be avoided, which drug classes will be favoured over others, which strategies are most likely to succeed, and the potential impact of pharmacogenomics and individualized therapy.