Current HIV treatment guidelines emphasize the importance of using an active antiretroviral therapy regimen that produces full virologic suppression and immunologic competence, while at the same time providing patients with a favorable safety profile and limited risk for development of drug resistance. Etravirine (TMC125), a recently approved, non-nucleoside reverse transcriptase inhibitor (NNRTI), has shown durable, superior virologic efficacy over placebo in the Phase III, randomized, double-blind DUET trials in 1,203 treatment-experienced, NNRTI-resistant, HIV-1-infected patients. Statistical significance of responses with etravirine over placebo was maintained through Week 24, 48 and 96, regardless of baseline demographics, baseline disease characteristics or the background regimen used. Etravirine has demonstrated a favorable safety and tolerability profile; the incidence of treatment-emergent adverse events was comparable with placebo in the DUET trials, with the exception of rash. The tolerability profile of etravirine also appears to be favorable in terms of neuropsychiatric and hepatic side effects. The pharmacokinetic profile of twice-daily etravirine minimizes the potential for clinically relevant drug-drug interactions and allows for its use in combination with a wide range of other agents. In addition, etravirine has a high genetic barrier to the development of resistance, further enhancing potential benefit in patients infected with NNRTI-resistant virus. The clinical efficacy and favorable safety profile of etravirine, together with its pharmacokinetic profile and high genetic barrier to resistance, make it a valuable treatment option for a wide range of treatment-experienced HIV-1-infected patients.