The first-generation non-nucleoside reverse transcriptase inhibitors (NNRTIs), efavirenz and nevirapine, fulfil key roles in antiretroviral therapy for HIV-infected paediatric patients, from lowering the incidence of mother-to-child transmission during pregnancy and birth to treatment throughout childhood and adolescence. Both agents have established efficacy, safety and tolerability profiles, and also offer advantages over other classes of therapy in terms of regimen simplicity and availability across different treatment settings. Although the role of NNRTIs in paediatric treatment strategies is largely determined by experience in adult patients, results of the recent phase II/III PENPACT-1 trial in infants and children aged between 30 days and 18 years have shown that there are no significant differences in 4-year virological, immunological or clinical outcomes between NNRTIs and protease inhibitors as first- and second-line agents. However, results from the IMPAACT P1060 study (cohort 2), conducted in resource-limited settings, showed that infants under 36 months unexposed to NNRTIs were significantly more likely to fail treatment when started on a nevirapine-based regimen than those on a lopinavir/ritonavir-based regimen. Unfortunately, the use of efavirenz and nevirapine in children can be limited by rapid development of high-level resistance to one or both agents, which may reduce the availability of viable treatment options, particularly in resource-limited settings. Several therapeutic strategies addressing this issue are currently under investigation, but a significant need for new NNRTI-based treatment options remains. The more recently approved NNRTI, etravirine, has demonstrated efficacy and safety benefits in HIV-1-infected, NNRTI-resistant adult patients, with a higher genetic barrier to the development of resistance relative to the first-generation NNRTIs. Another NNRTI, rilpivirine (TMC278), is approved for use in HIV-1-infected, treatment-naïve adult patients and has demonstrated an improved tolerability profile compared with efavirenz. Although available data on etravirine in children are currently limited, ongoing trials will provide important information on the potential for their use in novel paediatric treatment strategies. This review examines the role of efavirenz and nevirapine in paediatric antiretroviral therapy in children within different treatment settings. In addition, this review also outlines available clinical data on etravirine and rilpivirine in the context of how these antiretrovirals may address some of the limitations of efavirenz and nevirapine in paediatric patients.