HIV-1 reverse transcriptase (RT) was the first viral enzyme to be targeted by anti-HIV drugs. Despite 20 years of experience with RT inhibitors, new ways to inhibit this target and address viral resistance continue to emerge. In both licensed RT inhibitor classes, nucleosides (NRTIs) and non-nucleosides (NNRTIs), compounds with better resistance, pharmacokinetic and toxicity profiles are being developed. Second-generation NNRTIs active against HIV-1 strains resistant to current NNRTIs are being clinically evaluated. Beyond the classical NRTIs, nucleoside analogs that are no longer obligate chain terminators but nevertheless impede reverse transcription or even lead to viral ablation after several replication cycles, are being studied. RT inhibitor research has also yielded additional mechanisms to block RT. Driven by new insights the RNase H field remains in evolution. In addition, the binding of both substrates (deoxynucleotide and primer/template) to RT is now subject to competition by novel inhibitors. Further development of aptamers bears promise for gene therapy but perhaps more importantly, reveals additional new platforms for the development of small-molecule RT inhibitors. This promising research provides much optimism that RT inhibitors will continue to evolve with subsequent clinical benefit.