Rilpivirine (RPV) is a second-generation non-nucleoside reverse transcriptase inhibitor (NNRTI). It remains active against HIV strains harbouring mutations that affect first-generation agents. RPV is dosed once daily with food and has been coformulated into a single tablet containing tenofovir and emtricitabine. Two Phase III studies of treatment-naive patients found RPV and efavirenz to have similar safety and efficacy. However, suboptimal virological suppression with RPV occurred more commonly in patients with higher baseline viral loads (>100,000 copies/ml). The most common mutation that emerged during RPV therapy was E138K, which often occurred in combination with M184I. E138K is likely to cause cross-resistance to other NNRTIs thereby limiting the further utilization of this class.