Rilpivirine is a novel second-generation nonnucleoside reverse transcriptase inhibitor that has been recently approved for the treatment of HIV-1-infected patients. Rilpivirine combined with two nucleoside/nucleotide reverse transcriptase inhibitors has been evaluated as first-line therapy in two phase III clinical trials and has demonstrated non-inferior efficacy versus efavirenz, as well as a more favorable toxicity profile. Furthermore, rilpivirine has also been marketed in co-formulation with tenofovir and emtricitabine in a fixed-dose single-tablet regimen, improving the convenience of this combination and making it an attractive first-line option for treatment-naive patients. It could also be a convenient, effective option for treatment switch strategies. The efficacy of rilpivirine is lower, however, in patients with viral loads greater than 100,000 copies/ml at baseline because of a higher virologic failure rate. In addition, the percentage of new resistance-associated mutations (for both nucleoside/nonnucleoside reverse transcriptase inhibitors) emerging at virologic failure is higher in patients receiving rilpivirine than in those failing efavirenz, mainly in patients with baseline viral load greater than 100,000 copies/ml. Furthermore, when resistance to rilpivirine is selected after virologic failure, cross-resistance to all nonnucleoside reverse transcriptase inhibitors is commonly observed. In addition to these aspects, certain pharmacokinetic issues must be taken into account when rilpivirine is used. The aim of this review is to highlight the strengths and limitations of rilpivirine that should be taken into account in clinical practice in order to optimize its use within the extensive panel of therapeutic options for HIV-1-infected patients.