Despite major efforts by academic and pharmaceutical research teams, no definitive prevention or cure of AIDS has been achieved. Nevertheless, this research has yielded important information on how HIV replicates and causes disease. Moreover, several inhibitors, targeted at different steps in the life cycle of HIV, have been discovered, some of which have been licensed or are being studied in the clinic. One of the major obstacles towards more effective drugs or a vaccine, is the extraordinary variability in HIV strains which occur in different parts of the world over time, and in patients. The driving force behind these numerous variants is the combination of an error-prone reverse transcriptase, a viral enzyme transcribing the viral RNA genome into DNA on the one hand and the human immune system on the other hand. This puts a constant selection pressure on the HIV population leading to the emergence of escape mutants. It therefore poses an additional challenge on the discovery and development of HIV inhibitors. A research strategy should therefore encompass the following steps: (i) the identification of new lead compounds targeted at known or unknown steps in the HIV replicative cycle, (ii) the characterization and validation of their molecular targets with emphasis on the potential for lead optimization and the likelihood of resistance development, (iii) the study of combination strategies, and (iv) clinical evaluation and validation of the aforementioned concepts.