Despite the availability of 20 approved anti-retroviral drugs for the treatment of HIV infection, there is still a need for new anti-retrovirals to improve convenience, reduce toxicity and, of particular importance, to provide activity against the growing number of drug-resistant HIV strains. A new generation of potent HIV-1 non-nucleoside reverse transcriptase inhibitors (NNRTIs) is emerging that inhibit HIV-1 strains resistant to the NNRTIs that are prescribed today, and which provide a higher genetic barrier for resistance development than do their predecessors. Of several NNRTIs that are in preclinical and clinical development, two agents, capravirine and TMC125, have shown promise in early clinical trials. The persistent and systematic study of the capacity of HIV to evolve under drug pressure, combined with basic studies in the mode of action of NNRTIs, can provide new weapons in the fight against AIDS.