INTRODUCTION HIV therapy has evolved rapidly since the 1990s; the arrival of more potent and safer antiretroviral drugs has transformed HIV infection into a chronic condition, which is rarely fatal. Non-nucleoside reverse transcriptase inhibitors (NNRTIs) are frequently used as a third agent - as part of a triple-combination therapy. Side effects and low barriers to resistance have been the major drawbacks of NNRTIs. Rilpivirine (RPV) is a next-generation non-nucleoside analogue, the unique features of which might favor choosing this drug over other NNRTIs. RPV is the latest NNRTI approved for the treatment of HIV infection. Along with its high efficacy and good safety profile, data on pharmacokinetics and drug interactions make RPV particularly attractive. AREAS COVERED This article aims to provide an in-depth analysis of the main features and data available from recent clinical trials that have tested the performance of RPV. EXPERT OPINION RPV is a safe and efficacious antiretroviral drug with a better neuropsychiatric and metabolic profile than efavirenz, which is currently the most widely used NNRTI. The availability of a fixed-dose coformulation of RPV with tenofovir/emtricitabine makes the use of RPV even more attractive. The efficacy of RPV in patients with a high baseline viral load remains to be clarified in further trials.