BACKGROUND Etravirine is the first non-nucleoside reverse transcriptase inhibitor (NNRTI) to be active against human immunodeficiency virus with NNRTI mutations. OBJECTIVE To understand the unique features of etravirine and to evaluate its safety, efficacy, and optimal use. METHODS The structure and the mechanism of action of etravirine in blocking the reverse transcriptase enzyme and the preclinical, pharmacokinetic and pharmacodynamic studies were reviewed. The DUET Phase III clinical trials and the resistance profile of etravirine were evaluated. CONCLUSIONS Etravirine has unique activity against most HIV isolates that are resistant to other NNRTIs. Unlike other NNRTIs, it has a higher genetic barrier to developing high-grade resistance. In the DUET studies, etravirine demonstrated virological efficacy superior to the control arms with comparable rates of adverse events with the exception of rash. Because of its effect on the cytochrome P450 system, there are important drug interactions that will need to be taken into consideration with its use.