After 15 years of global scale-up of antiretroviral therapy (ART), rising prevalence of HIV drug resistance in many low-income and middle-income countries (LMICs) poses a growing threat to the HIV response, with the potential to drive an increase in mortality, HIV incidence, and costs. To achieve UNAIDS global targets, enhanced strategies are needed to improve quality of ART services and durability of available ART regimens, and to curb resistance. These strategies include roll out of drugs with greater efficacy and higher genetic barriers to resistance than those that are currently widely used, universal access to and improved effectiveness of viral load monitoring, patient-centred care delivery models, and reliable drug supply chains, in conjunction with frameworks for resistance monitoring and prevention. In this Review, we assess contemporary data on HIV drug resistance in LMICs and their implications for the HIV response, highlighting the potential impact and resistance risks of novel ART strategies and knowledge gaps.