Etravirine (ETR) is a new antiretroviral drug of the non-nucleoside reverse transcriptase inhibitor (NNRTI) family that has recently been approved by the regulatory agencies for the treatment of patients with prior experience with antiretrovirals, evidence of active viral replication, and who harbor multidrug resistant HIV-1 strains. In this context, in Europe, the use of this drug has been authorized combined with boosted protease inhibitors and nucleoside reverse transcriptase inhibitors. This approval was based on the results of the randomized double-blind DUET studies, in which the ETR arm was statistically superior to the placebo arms in terms of virological efficacy, immunological recovery, clinical progression and health- related quality of life. These studies showed that ETR was as well-tolerated as placebo, except for the appearance of rash, which was more common in the ETR arm. However, rash was usually mild or moderate and caused discontinuation of ETR in only 2% of the patients. The characteristics of ETR, i.e., potency, benign safety profile, resistance profile, pharmacokinetic characteristics, and drug interactions suggest that the use of this drug may go beyond its currently approved indications. Nevertheless, the evidence supporting these alternative uses is still scarce, although a randomized, double-blind, placebo controlled trial (SENSE) is under way in treatment-naïve patients. In this trial ETR will be administered once daily and the principal objective is to show that ETR has better tolerability in the central nervous system (CNS) than efavirenz. Moreover, the tolerability profile in the CNS, liver, and even skin suggest that ETR may be a good option when there are toxicity problems, or a risk of toxicity, with first-generation NNRTIs. When there is virological failure with an initial first-generation NNRTI-based regimen, the differential resistance profile of ETR may allow this drug to be used to construct a rescue combination. ETR is not teratogenic and can therefore be safely used in pregnant or fertile women. Finally, ETR has an excellent drug-drug interaction profile, which may be useful in patients administered other medications. This interaction profile may be especially important in areas with a high prevalence of methadone treatment, as both drugs can be coadministered safely. ETR has received approval as advanced rescue therapy. However, the characteristics of this drug suggest that it may be useful in a series of potential indications, due to its antiviral potency, differential resistance profile, safety, tolerability and drug-drug interaction profile.