Efavirenz non-nucleoside reverse transcriptase inhibitor (NNRTI)-based therapy or boosted protease inhibitor (PI)-based therapy are currently recommended as first-line regimens for the treatment of HIV infection. Although the available therapy options are efficacious and well-tolerated in the majority of patients, treatment durability is still limited by drug-related side effects, inadequate patient adherence and the development of drug resistance. PI-based regimens have higher tablet loads, more complicated drug interactions and have been associated with gastrointestinal side effects and metabolic abnormalities. NNRTI-based regimens are efficacious, but have a low genetic barrier to resistance and have been associated with rash, hypersensitivity reactions and central nervous system side effects. There is, therefore, still a need for first-line antiviral agents that facilitate patient adherence and allow durable suppression of viral replication. The next-generation NNRTIs in development include rilpivirine (TMC-278), UK-453061, RDEA-806, IDX-899 and MK-4965. These NNRTIs demonstrate significant advantages over efavirenz, and may improve treatment options for first-line therapy. A number of other structurally diverse compounds that inhibit common NNRTI-resistant mutant viruses are also under investigation. In this review, the desirable features of a next-generation NNRTI for treatment-naïve patients are discussed, as well as the properties of the NNRTIs that are currently in development.