HIV-positive children are at high risk of drug resistance, which is of particular concern in settings where antiretroviral options are limited. In this Review we explore resistance rates and patterns among children in developing countries in whom antiretroviral treatment has failed. We did a systematic search of online databases and conference abstracts and included studies reporting HIV-1 drug resistance after failure of first-line paediatric regimens in children (<18 years) in resource-poor regions (Latin America, Africa, and Asia). We retrieved 1312 citations, of which 30 studies reporting outcomes in 3241 children were eligible. Viruses with resistance-associated mutations were isolated from 90% (95% CI 88–93%) of children. The prevalence of mutations associated with nucleoside reverse transcriptase inhibitors was 80%, with non-nucleoside reverse transcriptase inhibitors was 88%, and with protease inhibitors was 54%. Methods to prevent treatment failure, including adequate paediatric formulations and affordable salvage treatment options are urgently needed.