The usefulness of every antiretroviral drug in the clinical setting should be continuously evaluated, since registration studies may not adequately reflect real-world patient populations. Rilpivirine was developed in an effort to generate patient-tailored drugs with high convenience and minimal side effects. By now, rilpivirine is currently licensed for use with other antiretroviral agents, and as a single agent or a single-tablet regimen with tenofovir and emtricitabine , in antiretroviral-naive, HIV-1-infected adults with < 100,000 HIV-1 RNA copies/ml because of a higher rate of virological failure above this level. However, after its introduction several questions remained to be elucidated, such as the efficacy of rilpivirine with abacavir/lamivudine, or its use in switching strategies, a useful alternative for patients with toxicity or intolerance. Cumulative data suggest the efficacy and safety of the combination of abacavir/lamivudine plus rilpivirine in the clinical setting, and an increasing number of patients received rilpivirine after protease inhibitor, efavirenz, or nevirapine-based therapy without compromising rilpivirine exposure after the change. Moreover, rilpivirine is a substrate and weak inducer of the CYP3A4, but there are no significant pharmacokinetic interactions with new anti-hepatitis C compounds such as telaprevir, simeprevir, daclatasvir, ledipasvir, and sofosbuvir, an important issue for a drug with low risk of hepatoxicity. As a new and promising strategy, rilpivirine has been evaluated with darunavir and dolutegravir in dual therapies, without need of dose adjustment and with adequate preliminary data. Therefore, to date, new data on rilpivirine confirm the good results observed in the clinical trials.